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Objective Despite the abundant literature on the associations between psychosocial work factors and mental health outcomes, prospective studies using medico-administrative data are lacking. Our objective was to study the associations between various psychosocial work factors and subsequent psychotropic drug prescription.Material and Methods The study was based on data from the three waves (2010, 2012, 2014) of the French ESPS survey (Enquête Santé et Protection Sociale) linked to the national database of healthcare reimbursements. Each survey wave was conducted among a randomly selected national sample of people aged 18+, and a subsample was interviewed twice (2010 and 2014). A total of 8094 workers free of depression at baseline were included. Ten psychosocial work factors (quantitative demands, tensions with the public, freedom, possibilities for learning new things, colleague support, recognition, salary satisfaction, job insecurity, permanent/temporary contract, and redundancy plan) were assessed at baseline. The outcome was psychotropic drug prescription within the 2 following years. As 1086 of these workers participated twice, Cox regression models for clustered data were used to assess the associations between psychosocial work factors and psychotropic drug prescription, after adjustment for age, marital status, employee/self-employed worker, private/public sector, occupation, full/part time work, and survey wave.Results Most psychosocial work factors, except possibilities for learning new things, job insecurity, and permanent/temporary contract, were associated with subsequent psychotropic drug prescription. The number of psychosocial work factors increased the risk of psychotropic drug prescription. No gender interaction was found for these associations. Associations were observed for antidepressants, anxiolytics, and hypnotics/sedatives.Conclusion The findings support that poor psychosocial working conditions may increase the risk of psychotropic drug prescription.Funding The French National Research Program for Environmental and Occupational Health of Anses (ANSES-23-EST-041)