Aim: The objective of this study was to develop and validate a brief tool, the Dual Diagnosis Screening Instrument (DDSI), to screen psychiatric disorders in substance users in treatment and nontreatment-seeking samples. Methods: A total of 827 substance users (66.5% male, mean age 28.6 ± 9.9 years) recruited in treatment (in- and outpatient) and nontreatment (substance user volunteers in university research studies) settings were assessed by trained interviewers using the DDSI and the Psychiatric Research Interview for Substance and Mental Disorders (PRISM) as the criterion standard. Both instruments were administered blind to the results of the other. Disorders obtained with the DDSI were compared to lifetime diagnoses obtained with the PRISM. Sensitivity, specificity, negative, and positive predictive values were estimated. Also test-retest reliability of the DDSI was assessed. Results: The DDSI showed a high sensitivity (=80%) for identifying lifetime depression, mania, psychosis, panic, social phobia, and specific phobia disorders. Specificity was =82% for those diagnoses. Test-retest κ showed excellent agreement (range 81-95%). The mean duration of the DDSI administration was 16.8 ± 2.5 min. Conclusion: The DDSI is a valid and easy-to-administer screening tool to detect possible psychiatric comorbidity among substance users.