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Background and objectives The prevalence of substance use disorders (SUD), particularly involving opiates and benzodiazepines, has increased to the detriment of public health and the economy. Here, we evaluate relapse factors among the high-risk demographic of patients with SUD and comorbid affective disorders. Methods A retrospective chart review of 76 patients discharged after detoxification and simultaneous psychiatric care for concomitant affective disorders and SUDs. Relapse was assessed by two independent evaluators via postdischarge chart review, which included state-wide healthcare utilization, by patient, through healthcare information exchange systems. A Cox Hazards analysis was performed to characterize relapse risk factors. Results Benzodiazepine use, admission through the emergency department (ED) rather than direct admission, frequent ED use in the preceding year, and history of prior attendance at multiple detoxification programs were risk factors for shortened time-to-relapse. Polysubstance use and intravenous drug use prolonged time to relapse. Discussion and conclusions Notable findings include the significant relapse risk associated with benzodiazepine abuse and frequent prior ED utilization. These risk factors could reflect a number of underlying mediators for relapse, including anxiety, disease burden, and malingering. Additionally, this study recapitulates the observation in other patient populations that the majority of health resource utilization is attributed to a small population of patients. Scientific significance This study is the first to identify relapse predictors among dual-diagnosis affective disorder and SUD patients in survival analysis, and replicates the alarming and largely unknown effect that benzodiazepines have on increasing relapse risk.