OBJECTIVE: Gender differences in psychosis have been investigated, and the results have contributed to a better understanding of the disease, but many questions are unanswered. In clinical terms, women and men with psychosis differ in terms of access to social support, tendency of substance abuse, level of functioning and symptom patterns. We aimed to investigate how gender differences at onset of psychosis develop during the first 5years of treatment. METHOD: A total of 578 patients with a first-episode psychosis in the schizophrenia spectrum were included in the Danish OPUS trial - a randomized clinical trial comparing 2years of intensive early-intervention programme with standard treatment. All patients were assessed with validated instruments at inclusion, and after 2 and 5years. Data were analysed for significant gender differences. RESULTS: Males have significantly higher levels of negative symptoms at all times, and are more likely to live alone and suffer from substance abuse. Females reach higher levels of social functioning at follow-up, and show a greater tendency to be employed or in education than males. Markedly more women than men live with children. More women than men reach a state of recovery and are more compliant with medication. CONCLUSION: There are significant gender differences at 2- and 5-year follow-up in this large cohort of first-episode psychotic patients. Males and females show different symptomatology and different levels of social functioning.