Objective To investigate the effects of co-exposure to biomechanical wrist stressors and chemicals on the risk of CTS in a large cohort of French workers. Methods Prospective study using the data collected at baseline and at the first 12 month-follow-up for the 18,018 participants included in the population-based Constances cohort between 2012 and 2015. CTS at follow-up and exposure to biomechanical wrist stressors and chemicals at baseline were assessed using a self-administered questionnaire. 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 184 men (2.1%, 95%CI 1.8-2.4) and 331 women (3.6%, 3.2-3.9) free from chronic hand symptoms at baseline declared suffering from unilateral/bilateral CTS at follow-up. A potentiating effect of co-exposure to biomechanical wrist stressors and chemicals on the risk of CTS was found for both genders, with higher OR in the co-exposure group (OR = 3.38 [2.29-5.01] in men and OR = 4.12 [2.73-6.21] in women) than in the biomechanical exposure group (OR = 2.14 [1.51-3.03] in men and OR = 2.19 [1.72-2.78] in women) compared to no exposure group.