Aim To assess the prevalence of exposure and co-exposure to physical constraints and neurotoxic chemicals in French workers and to study the association with carpal tunnel syndrome (CTS). Methods Data from the Constances cohort collected at baseline between 2012 and 2018 and at the first 12 month-follow-up were studied. Exposure to physical wrist stressors at baseline and CTS at follow-up were assessed using self-administered questionnaires. Exposure to neurotoxic chemicals was assessed by questionnaire and the job-exposure matrix Matgéné. Associations between CTS and co-exposure to biomechanical wrist stressors and chemicals were studied using multivariate logistic regression models, adjusted for personal/medical factors. Results Among active employees at baseline and at follow-up and free from chronic hand symptoms at baseline (9527 men and 13371 women), 164 men (1,7%) and 335 women (2,5%) declared suffering from unilateral/bilateral CTS at follow-up (p<0.0001). An association between co-exposure to biomechanical wrist stressors and chemicals and CTS was found for both genders. Discussion This finding will be confirmed using more objective case definition of CTS (e.g., surgery of CTS) and assessment of physical constraints and neurotoxic chemicals during the entire working life using job-exposure matrix. Conclusion The study showed an association between CTS and co-exposure to physical constraints and neurotoxic chemicals, after adjustment for the main personal and medical factors.