Objective: Few studies have evaluated moderators of mindfulness-based relapse prevention (MBRP) for substance use disorders (SUDs). We tested whether baseline patterns of scores for SUD symptom severity and depression and anxiety symptoms moderated the efficacy of MBRP. Method: We used a latent class moderation approach with data from a randomized trial of MBRP compared to cognitive–behavioral relapse prevention and treatment as usual (TAU; Bowen et al., 2014; N = 286, 71.8% male, 48.4% non-White, mean age = 38.44 years, SD = 10.92) and a randomized trial comparing MBRP to TAU (Bowen et al., 2009; N = 168, 63.7% male, 44.6% non-White, mean age = 40.45, SD = .28). Indicators for the latent class models were measures of SUD severity (Severity of Dependence Scale and Short Inventory of Problems), depression symptoms (Beck Depression Inventory), and anxiety symptoms (Beck Anxiety Inventory). Results: In both trials, 3 latent classes provided the best fit: a high–high class characterized by high SUD severity and depression and anxiety symptoms, a high–low class characterized by high SUD severity and low depression and anxiety symptoms, and a low–low class characterized by low SUD severity and depression and anxiety symptoms. In both trials, we found significant latent Class × Treatment interaction effects: There were significant and large effects of MBRP on substance use outcomes in the high–high and high–low classes, but no MBRP effect in the low–low class. Conclusion: MBRP may be an optimal treatment for preventing relapse among clients with severe levels of SUD symptoms and depression and anxiety symptoms, as well as clients with only severe SUD symptoms.