Poor medication adherence is problematic among HIV positive, low-income African-American substance users. Substance use has been shown to be associated with poor medication adherence, though we do not know the mechanism that underlies this relationship. Lack of positive environmental rewards and the propensity to discount delayed rewards may be possible mechanisms to explain this relationship. Using baseline data from a randomized controlled trial, we examined the relationships between substance use and medication adherence, testing both environmental rewards and delay discounting as independent mediators. There was a main effect of substance use on adherence, such that high frequency of substance use predicted poor adherence. There was also a main effect of environmental rewards on adherence, such that a lack of environmental reinforcement predicted poor adherence. This study shed light on the processes that contribute to low adherence, namely substance use and lack of environmental contingencies, and suggests important targets for intervention.