OBJECTIVE: We explored the relationship between HLA-DRB1 allele polymorphisms and familial aggregation of hepatocellular carcinoma (fhcc). METHODS: Polymerase chain reaction sequence-specific primers were used to determine HLA-DRB1 genotypes for 130 members of families with 2 or more liver cancer patients and for 130 members of families without any diagnosed cancers. The genotype profiles were then compared to explore the relationship between HLA-DRB1 gene polymorphism and fhcc. RESULT: Of 11 selected alleles, the frequencies of DRB1*11 and DRB1*12 were significantly lower in the fhcc group than in no-cancer group (p < 0.05; odds ratio: 0.286; 95% confidence interval: 0.091 to 0.901; and odds ratio: 0.493; 95% confidence interval: 0.292 to 0.893). Differences in the frequencies of the other 9 alleles were not statistically significant in the two groups (p > 0.05). CONCLUSIONS: Our research suggests that if genetic factors play a role in fhcc, the deficiency in the DRB1*11 and DRB1*12 alleles might be the risk factor at work in Guangxi Zhuang Autonomous Region, P.R.C.