We investigated the effects of three legal drugs (tobacco, caffeine, and alcohol) on the prevalence of carpal tunnel syndrome (CTS) confirmed by nerve conduction studies (definite CTS) in two groups of American industrial workers: 656 nonclaimant workers and 808 working patients referred for upper extremity symptoms. Comparing workers with definite CTS to workers without definite CTS revealed 26% greater current use of tobacco, 19% greater lifetime use of tobacco, 5% greater current use of caffeine, 14% lesser current use of alcohol, and 75% greater history of alcohol abuse in the workers with definite CTS. All these differences were statistically significant. Those who currently used alcohol but not tobacco or caffeine were at the lowest risk for slowing, symptoms, and definite CTS. Those who currently used caffeine alone or in combination with tobacco were at the highest risk. In female workers, current smoking, current caffeine use, and current coffee consumption independently predicted 5.0% of the explainable risk for definite CTS. In male workers, history of alcohol abuse and current beer consumption independently predicted 3.0% of the explainable risk for definite CTS. Prevalence of slowing, symptoms, and definite CTS in 12 specific job categories correlated directly with current tobacco use. We conclude that the use of legal drugs affects the prevalence of median nerve slowing, symptoms, and carpal tunnel syndrome, but the effects of the drugs independently explain only a small portion of the total risk. Nevertheless, legal drug use or abuse may serve as a marker for increased CTS risk.