Background and Aims: Patients with co-occurring substance use and other mental disorders are vulnerable to crime victimization, yet no evidence-based preventive interventions exist. Our aim was to test the efficacy of a new intervention, Self-wise, Other-wise, Streetwise training (SOS training), to prevent victimization in these dual-diagnosis patients as an add-on to care as usual. Design: Multi-site single-blind parallel randomized controlled trial. Setting: Three sites within one psychiatric service in Amsterdam, the Netherlands. Participants: Adult in-patients and out-patients with dual diagnosis (n = 250), who were predominantly male (70.4%), aged on average 42.1 years, and diagnosed with 3.7 DSM-IV disorders. Intervention and comparator: Care as usual, consisting of pharmacotherapy combined with individual psychotherapy, group psychotherapy and/or supportive counselling (n = 125) was compared with care as usual plus SOS training: a 6-week, 12-session manualized group training focused on enhancing emotion regulation skills, conflict resolution skills and street skills (n = 125). Measurements: Victimization was assessed with the Safety Monitor, the Dutch equivalent of the International Crime Victims Survey, in a face-to-face assessment. The primary outcome measure was treatment response (yes/no), with ‘yes’ defined as reporting at least a 50% reduction in the number of past-year victimization incidents at the 14-month follow-up compared with baseline. Analyses were performed according to the intention-to-treat principle. Findings: The proportion of participants achieving treatment response for total victimization was 54.0% in the control group and 67.6% in the experimental group, a significant difference [odds ratio (OR) = 1.78, 95% confidence interval (CI) = 1.02–3.11, P = 0.042]. Treatment response for violent victimization was achieved by 68.7% of the control group and 79.3% of the experimental group (OR = 1.75, 95% CI = 0.91–3.34, P = 0.092). With a Bayes factor of 2.26, this result was inconclusive. Conclusions: Among dual-diagnosis patients, care as usual plus Self-wise, Other-wise, Streetwise training was more effective in preventing victimization than care as usual alone.