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South Africa has the largest HIV burden and treatment program in the world. Diversion of HIV prevention and treatment medication for recreational use—or nonmedical use for psychoactive effects—is a public health concern globally and in South Africa. Few South African studies examine recreational use of HIV antiretrovirals (ARVs). The objective of this article is to evaluate the prevalence of recreational ARV use and to identify risk and protective factors associated with use. Data are drawn from a cross-sectional household survey of N = 4399 adolescent girls and young women (AGYW) aged 15–24 years in six districts across South Africa where an evaluation of a South African combination HIV prevention for girls and young women was implemented. The use of ARVs to "get high" was reported by 8.3% of AGYW across all districts. Logistic regressions showed that those engaging in transactional sex were at two times higher odds of recreational ARV use [adjusted odds ratio (aOR) = 2.01; confidence interval (95% CI): 1.51–2.68]. Recreational ARV use was more likely among those who used pre-exposure prophylaxis (PrEP) (aOR = 2.17; 95% CI: 1.36–3.48); HIV-positive participants who were not on ARVs for treatment (aOR = 0.36; 95% CI: 0.18–0.68); and those who were not virally suppressed (aOR, no vs. yes = 2.84; 95% CI: 1.21–6.66). As ARVs become more widely available for prevention and treatment, it will be important to monitor and address the possible emergence of ARVs as a substance for misuse or abuse. [ABSTRACT FROM AUTHOR]