<b>Objectives: </b>To<b> </b>investigate the factors affecting adherence to antiretroviral therapy (ART) and the quality of life in people living with human immunodeficiency virus (HIV), with a focus on evaluating the mediating roles of positive self-care management (PSCM) and brain gym.<br />
<b>Methods:</b> This is a descriptive study with a cross-sectional design. The data collected from June to August 2023. There are 262 respondents selected through convenience sampling. We used various research instruments, including questionnaires, which have undergone validity and reliability testing. The data were analyzed using the SEM-PLS analysis method.<br />
<b>Results: </b>Our data analysis shows that condition factors, physical and social environmental factors, and individual and family factors affect HIV individuals’ PSCM and brain gym combination, ART adherence, and quality of life. Findings show that condition-specific factors indirectly affect antiretroviral drug adherence. This impact is mediated by PSCM and brain gym.<br />
<b>Conclusions: </b>Specific condition variables, namely<b><i> </i></b>complexity of the disease, barriers, and stability of conditions indirectly influence ART adherence, mediated through the combined influence of PSCM and brain gym. This finding suggests that to enhance adherence and the quality of life among PLHIV, it is important to adopt an approach that encompasses a range of internal and external individual factors.<b> </b>