Background: Exploratory study to investigate whether co-exposure to physical wrist stressors and chemicals is associated with carpal tunnel syndrome (CTS) in French male farmers and agricultural workers. Methods: Cross-sectional study of 711 men aged 30–65 years and working as either farmers or agricultural workers in 2009–2010 within a cohort covered by the French Agricultural Workers' and Farmers' Mutual Benefit Fund. CTS and exposure to physical wrist stressors and chemicals were assessed using a self-administered questionnaire. Associations between CTS and personal/medical factors, exposure to physical wrist stressors, exposure to chemicals, and co-exposure to physical wrist stressors and chemicals were studied using multivariate logistic regression models. Results: Forty-four men {5.6% [95% confidence interval (CI) 4.0–7.7]} reported that they had suffered from unilateral/bilateral CTS during the last 12 months. CTS was associated with age, current smoking [odds ratio (OR) = 2.1 (1.0–4.5)], and exposure to physical wrist stressors [OR = 2.6 (1.1–5.9)]. An association was found between CTS and co-exposure to physical wrist stressors and chemicals [OR = 3.3 (0.8–14.3), p = 0.044] in comparison with the no-exposure group. Conclusions This exploratory study shows an association of CTS with exposure to biomechanical wrist stressors in male farmers and agricultural workers and suggests an association of CTS with co-exposure to physical wrist stressors and chemicals. Owing to the limitations of the study, this result must be confirmed by a prospective study with objective assessments of the outcome and exposure before drawing conclusions on the possible synergistic effects of mechanical stressors and chemicals on the impairment of the median nerve.