Previous laboratory investigations, case reports, and a hospital-based case-control study have suggested that marijuana use may be a risk factor for squamous cell head and neck cancer. We conducted a population-based case-control study to determine whether marijuana use is associated with the development of oral squamous cell carcinoma (OSCC). Case subjects (n = 407) were 18-65-year-old residents of three counties in western Washington State who were newly diagnosed with OSCC from 1985 through 1995. Control subjects (n = 615), who were similar to the cases with respect to age and sex, were selected from the general population using random-digit telephone dialing. Lifetime histories of marijuana use and exposure to known OSCC risk factors were ascertained using a structured questionnaire. Information on genetic polymorphisms in glutathione S-transferase enzymes was obtained from assays on participant DNA. Odds ratios for associations with features of marijuana use were adjusted for sex, education, birth year, alcohol consumption, and cigarette smoking. A similar proportion of case subjects (25.6%) and control subjects (24.4%) reported ever use of marijuana (adjusted odds ratio, 0.9; 95% confidence interval, 0.6-1.3). There were no trends in risk observed with increasing duration or average frequency of use or time since first or last use. No subgroup defined by known or suspected OSCC risk factors (age, cigarette smoking, alcohol consumption, and genetic polymorphisms) showed an increased risk. Marijuana use was not associated with OSCC risk in this large, population-based study.