Primary hepatocellular carcinoma (PHC) is extremely common in eastern China, where it is both associated with chronic infection with hepatitis B virus (HBV) and often familial. Complex segregation analysis of 490 extended families was undertaken with liability classes defined by age, sex, and HBV infection status. The maximum-likelihood model suggests that a recessive allele with population frequency approximately .25 yields lifetime risk of PHC, in the presence of both HBV infection and genetic susceptibility, of .84 for males and .46 for females. The model further predicts that, in the absence of genetic susceptibility, lifetime risk of PHC is .09 for HBV-infected males and .01 for HBV-infected females and that, regardless of genotype, it is virtually zero for uninfected persons. Complex segregation analysis therefore provides evidence for the interaction of genotype, environmental exposure, sex and age in determining the occurrence of PHC in this population.