BACKGROUND: The purpose of this study was to assess the prevalence of psychological distress in medical students during the COVID-19 health crisis and to identify factors associated with psychological distress. METHODS: A cross-sectional observational study was presented to 1814 medical students (from first to sixth year) in a French university hospital center. Sociodemographic, occupational and medical information (psychological distress measured on the French GHQ12 scale) were collected via an online anonymous self-administered questionnaire. Variables associated with psychological distress were investigated using univariate analysis and multivariate analysis (modified Poisson regression). RESULTS: In total, 832 medical students responded (46%) and 699 completed the questionnaire in full (39%); 625 (75%) showed signs of psychological distress and 109 (15%) reported suicidal ideation. Female gender, psychological trauma during the COVID-19 health crisis, change in alcohol consumption, and difficulties with online learning emerged as risk factors for psychological distress, whereas a paid activity, a feeling of mutual aid and cooperation within the studies framework, and recognition of work appeared to be protective factors. CONCLUSIONS: Mental health care or suicide prevention should be provided to students at risk in the aftermath of the pandemic. Knowing the educational and medical factors associated with psychological distress enables areas for prevention to be identified.