Objectives: A qualitative study of the BREATHER (PENTA 16) randomised clinical trial, which compared virological control of Short Cycle Therapy (SCT) (5 days on: 2 days off) with continuous efavirenz (EFV)-based antiretroviral therapy (CT) in children and young people (aged 8-24) living with HIV with viral load <50 c/mL to examine adaptation, acceptability and experience of SCT to inform intervention development. Setting: Paediatric HIV clinics in the UK (2), Ireland (1), the USA (1) and Uganda (1). Participants: All BREATHER trial participants who were over the age of 10 and aware of their HIV diagnosis were invited to participate. 49 young people from both arms of the BREATHER trial (31 females and 18 males; 40% of the total trial population in the respective sites; age range 11-24) gave additional consent to participate in the qualitative study. Results: Young people from both trial arms had initial concerns about the impact of SCT on their health and adherence, but these decreased over the early months in the trial. Young people randomised to SCT reported preference for SCT compared with CT pre-trial. Attitudes to SCT did not vary greatly by gender or country. Once short-term adaptation challenges were overcome, SCT was positively described as reducing impact of side effects, easing the pressure to carry and remember medication and enabling more weekend social activities. Young people on both arms reported frequent medication side effects and occasional missed doses that they had rarely voiced to clinical staff. Participants liked SCT by trial end but were concerned that peers who had most problems adhering could find SCT disruptive and difficult to manage. Conclusions: To realise the potential of SCT (and mitigate possible risks of longer interruptions), careful dissemination and communication post-trial is needed. SCT should be provided alongside a package of monitoring, support and education over 3 months to allow adaptation.