Background Antiretroviral therapy has transformed human immunodeficiency virus infection intoa chronic condition associated with normal life expectancy. In the United Kingdom, the uptake of antiretroviral therapy is generally high, but a delay in starting antiretroviral therapy and non-adherence compromise the health and well-being of people living with human immunodeficiency virus, increase the risk of transmission of human immunodeficiency virus and increase National Health Service costs. Objectives The overall aim was to improve antiretroviral therapy uptake and adherence by addressing perceptual and practical barriers. The objectives were to (1) identify culturally specific beliefs and other factors influencing uptake of and adherence to antiretroviral therapy that have not emerged in previous research; (2) refine existing methods for assessing perceptual and practical barriers to antiretroviral therapy uptake and adherence; (3) develop an intervention to increase antiretroviral therapy uptakeand adherence; (4) determine intervention feasibility and acceptability; (5) evaluate intervention efficacy;(6) assess the short- and long-term costs and cost-effectiveness of the interventions and (7) prepare for implementation within the National Health Service. Design Objective 1 – in-depth interviews with Black African and Black Caribbean people living with human immunodeficiency virus ( n = 52); objective 2 – adaptation of the Beliefs about Medicines Questionnaire; objective 3 – development of the Supporting UPtake and Adherence to antiretroviral therapy service intervention; objective 4 – feasibility study ( n = 213) and acceptability/process interviews ( n = 24); objective 5 – observational study ( n = 484) and randomised controlled trial ( n = 143); objective 6 – systematic review, cost-effectiveness analysis ( n = 210) and economic modelling; and objective 7 – preparatory implementation work with people living with human immunodeficiency virus and human immunodeficiency virus clinic staff. Setting National Health Service human immunodeficiency virus clinics in England with a high proportion of ethnic minority populations. Participants People living with human immunodeficiency virus. Interventions Adherence support – cognitive–behavioural therapy plus care as usual. Main outcome measures Workstream 1 – adapted Beliefs about Medicines Questionnaire–antiretroviral therapy. Workstream 2 – feasibility study: participant recruitment and withdrawal rates. Workstream 3 – randomised controlled trial – primary outcome: medication event monitoring system adherence. Workstream 4 – incremental cost-effectiveness ratio. Results Workstream 1 – qualitative studies were used to refine the Beliefs about Medicines Questionnaire – antiretroviral therapy and, together with our preparatory research, to inform the cognitive–behavioural therapy-based intervention. Workstream 2 – recruitment to the randomised controlled trial and observational study was deemed feasible. Thematic analysis of exit interviews with recipients of the SUPA intervention demonstrated that the intervention was acceptable and addressed perceptual and practical barriers to antiretroviral therapy. In Workstream 3, we did not meet the recruitment targets and our trial was underpowered for the primary outcome: 143 participants met the inclusion criteria and were randomised (care as usual, n = 72; care as usual plus cognitive–behavioural therapy, n = 71). There was no significant effect of cognitive–behavioural therapy on the primary end point. Of the 112 participants (care as usual, n = 55; cognitive–behavioural therapy, n = 57) for whom sufficient data for primary end-point analysis were available, 17 (15.2%) met the primary end point (> 80% of months with an average monthly adherence of ≥ 90%) [9 (16.4%) in the care-as-usual group and 8 (14.0%) in the cognitive–behavioural therapy group ( p = 0.94)]. Secondary end points: median Medication Event Monitoring System adherence at 12 months was 61.9% in the care-as-usual group and 66.5% in the cognitive–behavioural therapy group ( p = 0.40), representing a 7.5% uplift in adherence. Participants who were randomised to receive the intervention, based on perceptions of antiretroviral therapy at baseline (low antiretroviral therapy necessity beliefs, and/or high antiretroviral therapy concerns), experienced a greater decrease in antiretroviral therapy concerns [care as usual −0.9 (95% confidence interval −1.4 to −0.5) vs. cognitive–behavioural therapy −0.6 (95% confidence interval −0.8 to −0.3); p = 0.03], treatment intrusiveness [median change in highly active antiretroviral treatment (antiretroviral therapy) Intrusiveness Scale scores: care as usual −0.5 (95% confidence interval −5.6 to 18.0) vs. cognitive–behavioural therapy −5.6 (95% confidence interval −20.4 to 1.2); p = 0.03] and depression scores [median change in depression score: care as usual 0 (95% confidence interval −1.5 to 2.0) vs. cognitive–behavioural therapy −1 (95% confidence interval −3 to 0); p = 0.02] between baseline and 12 months. Workstream 4 – cognitive–behavioural therapy resulted in 0.056 more quality-adjusted life-years than care as usual (95% confidence interval 0.0029 to 0.083). The incremental cost-effectiveness ratio was £11,189 per quality-adjusted life-year. At a threshold of £20,000 per quality-adjusted life-year, there was > 90% likelihood that the intervention would be more cost-effective than care as usual. There was a 13% likelihood that the intervention would produce more quality-adjusted life-years and result in lower health and social care costs than care as usual. A Markov model showed that, over the longer term, cognitive–behavioural therapy results in fewer quality-adjusted life-years and higher costs and, therefore, care as usual would be the more cost-effective option. Limitations Our primary outcome of full Medication Event Monitoring System adherence was problematic, our randomised controlled trial was underpowered and we were unable to demonstrate a significant difference in our primary outcome. Conclusions Patients who received the Supporting UPtake and Adherence to antiretroviral therapy service intervention benefited from a reduction in antiretroviral therapy concerns, a reduction in antiretroviral therapy intrusiveness and reduced depressive symptoms, and from improved quality of life. The intervention was likely to be cost-effective for the National Health Service within 12 months. Future work Given the difficulty in recruiting people at a high risk of non-engagement with human immunodeficiency virus care, future work assessing the effectiveness of adherence interventions may require alternative, non-standard randomised controlled trial designs. Further studies are necessary to recalibrate our understanding of the levels of antiretroviral therapy adherence necessary to achieve viral load suppression. Study registration The trial is registered as ISRCTN35514212 and the study is registered as CRD42019072431. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: RP-PG-0109-10047) and is published in full in Programme Grants for Applied Research ; Vol. 13, No. 8. See the NIHR Funding and Awards website for further award information.