Although the etiologic importance of tobacco in risk of upper aerodigestive malignancies is unquestioned, quantification of subsite-specific risks is less well delineated. Risk estimates from this case-control study are derived from self-administered comprehensive risk factor questionnaires distributed to newly registered patients at The University of Texas M.D. Anderson Hospital and Tumor Institute, Houston. Cases included 185 white patients with histologically confirmed squamous cell carcinoma of the upper aerodigestive tract. An equal number of age-frequency and sex-frequency matched patients was randomly selected from the same patient population excluding only patients with diagnoses of squamous cell carcinoma of any site. A statistically significant dose-response relationship for three categories of cigarette pack-years was evident for both males (odds ratios [OR] = 1.8, 4.0, and 7.5) and females (OR = 1.5, 9.0, and 12.0). Highest risks were documented for laryngeal cancer (OR = 15.1) and lingual cancer (OR = 14.5). There was interaction between alcohol use and smoking among men, but no independent effect of alcohol consumption among either gender. After 15 years of smoking abstinence, males no longer exhibited increased risk (OR = 1.0) whereas the risk for females after 15 years of cessation was 1.5. There were also significantly increased risks among men associated with snuff dipping, cigar, and pipe use (OR = 3.4, 2.8, and 1.8, respectively). The differences in the magnitude of the risk estimates and dose-response curves by subsite and by sex suggest a variable susceptibility to carcinogenic action.