Background Understanding adolescent decision-making processes is crucial for designing effective clinical trials that cater to their unique needs and perspectives.  Adolescents are at high risk for contracting HIV where their behaviours, perceptions and attitudes could influence treatment responses and long-term health outcomes. Therefore, integrating adolescent perspectives is critical in clinical research, yet, adolescent perspectives remain underrepresented in clinical trials. This study addresses this gap by examining the drivers and barriers to clinical research participation among adolescents and their parents/guardians in Rustenburg, South Africa.. Methods We conducted 6 focus group discussions (FGDs) with 55 participants consisting of separate sessions for 36 adolescents (12-19 years) and 19 parents/guardians to ensure open dialogue within each group.  At baseline (April to July 2018), we conducted two FGDs with adolescents (N=17) and two FGDs with parents/guardians (N=19). At endline (August to November 2019), we conducted an additional two FGDs with a different group of adolescents (N=19). Conducting FGDs at these two timepoints helped identify attributes before and after trial participation.  Thematic analysis guided by the COM-B (Capability, Opportunity, Motivation - Behaviour) framework was used to examine factors influencing adolescent participation in clinical research in Rustenburg. The analysis used both deductive coding based on COM-B components and inductive approaches to capture additional themes.  Using QSR NVIVO 12 and 14 qualitative analysis software, we conducted iterative coding of FGD transcripts and debrief notes to identify, categorise, and refine themes related to capabilities (knowledge and skills), opportunities (physical and social environment), and motivations (reflective and automatic) that influence research participation decisions. Results We conducted FGDs with 36 adolescents (24 females, 12 males; median age 17.5 years, IQR 15-18) and 19 parents/guardians (17 females, 2 males; median age 37 years, IQR 34-46). Analysis using the COM-B framework revealed how capability, opportunity, and motivation influenced research participation. Psychological capability improved through knowledge acquisition, with adolescents demonstrating enhanced understanding of clinical research from baseline to endline. Physical and social opportunities manifested through access to healthcare services and community engagement, with community leaders' endorsement playing a pivotal role. Reflective motivation emerged through altruism, while automatic motivation was evident in emotional responses. Barriers included limited psychological capability (lack of awareness about research processes), restricted physical opportunities (logistical challenges with transportation and school schedules), and negative automatic motivations (fear and mistrust). Initial high levels of fear decreased by endline, while mistrust rooted in past experiences and community narratives remained persistent. These themes emerged consistently across baseline and endline FGDs, with variations between adolescents and parents/guardians. Conclusions Our results highlight the importance of integrating adolescent preferences when designing clinical trials to enhance enrolment and retention. Analysed through the COM-B framework, the study's cross-sectional design revealed that participation itself can increase capability (knowledge and awareness) and motivation (trust) over time. Researchers should prioritize effective, age-appropriate communication strategies, community engagement, and flexible logistics to address identified barriers to capability, opportunity, and motivation. These insights can guide the development of more inclusive and supportive research environments, particularly crucial in South Africa with its large youth population.

The authors have declared no competing interest.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study was approved by the University of the Witwatersrand, Human Research Ethics Committee (ref. no 170607), and the Research Committee of the Northwest Provincial Department of Health.

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