BACKGROUND: The misuse of prescription psychostimulants (PPs) is growing among medical students, who are subject to high levels of stress, not least because of a demanding and competitive educational environment. AIM: To investigate this phenomenon among medical students in Belgium to identify misuse risk factors. METHOD: We conducted a cross-sectional study using an online questionnaire from 7 march 2023 to 3 April 2023. A semi-quantitative questionnaire based on a literature review and consultation with experts was drawn up, including the Perceived Stress Scale (PSS-10) and the Big Five Inventory (BFI-10). The questionnaire was administered to 323 final-year medical students (61.9% of whom responded) and comparatively to 325 second-to-last-year students and 205 first-year students (response rate was 36.9% and 18.5%, respectively). Descriptive and bivariate analyses were performed with Jamovi (version 2.3.21). RESULTS: Use of PPs increased over the years. In the final year, 12.6% reported that they had already used PPs to improve their cognitive performance, and 3.6% were currently using them. Various risk factors were associated with the misuse of PPs, including lack of consciousness, sensation-seeking, other substances use, high stress levels, social influence, curriculum high standards perception, and lack of ethical concern regarding the substance use. CONCLUSION: This study showed that more than one in ten final-year students have used PPs at least once during their studies, which can be explained mainly by challenging medical education context and personality traits. Tailored preventive strategies should be implemented. © British Journal of General Practice 2024.