Medication adherence is highly predictive of health outcomes across chronic conditions, particularly HIV/AIDS. Depression is consistently associated with worse adherence, yet few studies have sought to understand how depression relates to adherence. This study tested three components of behavioral depression theory—goal-directed activation, positive reinforcement, and environmental punishment—as potential indirect effects in the relation between depressive symptoms and medication nonadherence among low-income, predominantly African American substance users (n = 83). Medication nonadherence was assessed as frequency of doses missed across common reasons for nonadherence. Non-parametric bootstrapping was used to evaluate the indirect effects. Of the three intermediary variables, there was only an indirect effect of environmental punishment; depressive symptoms were associated with greater nonadherence through greater environmental punishment. Goal-directed activation and positive reinforcement were unrelated to adherence. Findings suggest the importance of environmental punishment in the relation between depression and medication adherence and may inform future intervention efforts for this population.