BACKGROUND: It has been suggested that there is a causal association between isotretinoin therapy and the risk of depression, psychotic symptoms, suicide, and attempted suicide. OBJECTIVE: To further investigate the proposed association between isotretinoin therapy and the risk of depression, psychotic symptoms, suicide, and attempted suicide using a formal study design. DESIGN: Large population-based cohort studies. SETTING: The Canadian Saskatchewan Health Database and the United Kingdom General Practice Research Database. PATIENTS: Data were analyzed for 7195 isotretinoin users and 13,700 oral antibiotic users with acne from the Canadian Saskatchewan Health Database and for 340 isotretinoin users and 676 oral antibiotic users with acne from the United Kingdom General Practice Research Database. All subjects had computer-recorded histories of between 6 months and 5 years before, and at least 12 months after, their first isotretinoin or antibiotic prescription. OUTCOME MEASURE: Prevalence rates of neurotic and psychotic disorders, suicide, and attempted suicide were compared between isotretinoin and antibiotic users and within isotretinoin users as their own comparison (pretreatment vs posttreatment). The results were expressed as relative risks, calculated using multiple logistic regression analyses. RESULTS: Relative risk estimates, comparing isotretinoin use and oral antibiotic use with nonexposure to either drug for newly diagnosed depression or psychosis, were approximately 1.0 regardless of the data source. Similarly, relative risk estimates were all around 1.0 when comparing before with after isotretinoin use. The relative risk estimate for suicide and attempted suicide was 0.9 (95% confidence interval, 0.3-2.4) when comparing current isotretinoin exposure with nonexposure. CONCLUSION: This study provides no evidence that use of isotretinoin is associated with an increased risk for depression, suicide, or other psychiatric disorders.