It is important to understand the factors affecting willingness of adolescents and youths to adhere to antiretroviral therapy (ART) in order to ensure positive treatment outcomes. Drawing on the Health Belief Model (HBM) theory, this study investigated the influence of self-efficacy and perceived benefits on the adherence to ART medications among adolescents and youths in Buffalo City Metropolitan Municipality (BCMM) District, Eastern Cape, South Africa. A purposive sample of 206 HIV positive adolescents and youth between age 14 to 24 years receiving ART in Buffalo City Metropolitan Municipality were interviewed using a self- administered questionnaire covering treatment benefits and self-efficacy. The majority of the participants affirmed strict adherence to the treatment plan is essential for effective ARV treatment (69.4%). The participants always take their medication on schedule (88.8%). It was found that a significant relationship exists between self-efficacy and adherence to ART (p = 0.000). The results suggest that perceived benefits and self-efficacy are a predictor of adherence to ART by adolescents and youths, at least in this setting.