Aims: To evaluate computer- versus therapist-delivered psychological treatment for people with comorbid depression and alcohol/cannabis use problems. Design: Randomized controlled trial. Setting: Community-based participants in the Hunter Region of New South Wales, Australia. Participants: Ninety-seven people with comorbid major depression and alcohol/cannabis misuse. Intervention: All participants received a brief intervention (BI) for depressive symptoms and substance misuse, followed by random assignment to: no further treatment (BI alone); or nine sessions of motivational interviewing and cognitive behaviour therapy (intensive MI/CBT). Participants allocated to the intensive MI/CBT condition were selected at random to receive their treatment ‘live’ (i.e. delivered by a psychologist) or via a computer-based program (with brief weekly input from a psychologist). Measurements: Depression, alcohol/cannabis use and hazardous substance use index scores measured at baseline, and 3, 6 and 12 months post-baseline assessment. Findings: (i) Depression responded better to intensive MI/CBT compared to BI alone, with ‘live’ treatment demonstrating a strong short-term beneficial effect which was matched by computer-based treatment at 12-month follow-up; (ii) problematic alcohol use responded well to BI alone and even better to the intensive MI/CBT intervention; (iii) intensive MI/CBT was significantly better than BI alone in reducing cannabis use and hazardous substance use, with computer-based therapy showing the largest treatment effect. Conclusions: Computer-based treatment, targeting both depression and substance use simultaneously, results in at least equivalent 12-month outcomes relative to a ‘live’ intervention. For clinicians treating people with comorbid depression and alcohol problems, BIs addressing both issues appear to be an appropriate and efficacious treatment option. Primary care of those with comorbid depression and cannabis use problems could involve computer-based integrated interventions for depression and cannabis use, with brief regular contact with the clinician to check on progress.