Although studies have consistently shown a strong relationship between medication nonadherence and substance abuse in psychotic disorders, less is understood about the mechanisms underlying this relationship. The purpose of this study was to examine whether the relationship between substance abuse and medication nonadherence in psychosis is mediated by depressive symptoms and social stability. Participants interviewed (N = 528) were adults with schizophrenia and related disorders receiving public mental health services in four US states. Multivariate analyses showed substance abuse, depressive symptoms, and living stability each contributed to medication nonadherence; thus, the relationship between substance abuse and medication adherence in psychotic disorders did not appear to be mediated by the selected variables. Instead, a robust association between depressive symptoms and medication adherence was found, attesting to the utility of assessing for depression when evaluating adherence among people with psychosis. Living instability was common and related to medication nonadherence, too, warranting further investigation.