This study evaluated whether the codon 72 p53 polymorphism was related to hepatocellular carcinoma (HCC). Genotypes of p53 were determined in 80 incident cases of HCC and 328 controls nested in a cohort study of 4,841 male chronic hepatitis B carriers. No overall increase in HCC risk with the Pro variant allele of the p53 polymorphism was apparent. However, there were synergistic effects on HCC development for the Pro allele with chronic liver disease and family history of HCC in first-degree relatives. Compared with subjects without the Pro allele and chronic liver disease, the increase in HCC risk associated with chronic liver disease among those without the Pro allele was only threefold. Subjects with both chronic liver disease and the Pro allele were at an increased risk of 7.60 (95% CI = 2.28-25.31). When subjects without family history of HCC and the Pro allele were considered as the reference group, there was no apparent increased risk of HCC for those without the Pro allele who had family history of HCC. Among those with both factors, there was a significantly increased risk of 3.29 (95% CI = 1.10-9.85). Both cigarette smoking and glutathione S-transferase M1 genotype modified the risk of HCC associated with the p53 polymorphism. Significantly increased risk associated with the p53 genotype was observed only among smokers who were glutathione S-transferase-null (Pro/Pro vs. Arg/Arg: odds ratio = 6.46; 95% CI = 1.55-26.94). The p53 polymorphism also interacted with the cytochrome P450 1A1 and carotenoid levels in smoking-related hepatocarcinogenesis.