Tobacco consumption is an established risk factor for cancer at a number of sites: oral cavity, esophagus, nasopharynx, lung, larynx, pancreas, bladder, kidney, and uterine cervix. These sites also demonstrate familial aggregation. To determine if evidence exists for a major gene controlling susceptibility to smoking-associated cancers, maximum likelihood segregation analyses were performed on 337 families (3,276 individuals) ascertained through a deceased lung cancer proband. Models were fitted that allowed for personal tobacco use and variable age of onset. The hypotheses of environmental transmission and no major gene were rejected (P < 0.005), but none of the Mendelian models could be distinguished. According to Akaike's Information Criterion, Mendelian dominant inheritance of an allele that produces cancer at an earlier age of onset provided the best fit to the data. The model suggests that 62% of the population are susceptible, and that the mean age-of-onset differs for men and women: at the mean level of tobacco exposure, female gene carriers are affected, on average, 24 years earlier than non-carriers (77 vs. 101), while in males the difference was 20 years (71 vs. 91). These findings extend our earlier observations on the genetic epidemiology of lung cancer and suggest that Mendelian factors may influence the risk of cancers that are known to be smoking associated.