Abstract: Objective To study the relationship between family clustering of hepatocellular carcinoma（HCC）and glutathione S-transferase M₁ and T₁ polymorphisms，to explore gene-gene interactions in HCC，and to assess differences in HCC risk between probands and first-degree relatives. Methods Peripheral blood samples were collected from 76 members of 21 HCC-clustering families and 68 members of 21 control families in the Zhuang population of Fusui county，Guangxi province.This area has a high incidence of HCC.M₁ and T₁ genotypes were determined by multiplex polymerase chain reaction，and serum HBsAg was measured by ELISA. Genotypes and clinical data were analyzed statistically to search for associations. Results The frequency of the GSTM1 null genotype was 67.1% in the family constellation of the HCC group and 36.8% in controls（P = 0.000）.The frequency of the GSTT₁ null genotype was 40.8% in the family constellation of the HCC group and 13.2 % in controls（P = 0.005），while the prevalence of the combined GSTM₁ and GSTT₁ null genotype was 31.6% and 2.9%（P=0.000）.Frequencies of the GSTM₁ or GSTT₁ null genotype and of the com-bined GSTM₁ and GSTT₁ null genotype did not differ significantly between probands and first-degree relatives. Conclusions ①A re-lationship was found between familial clustering of HCC and frequencies of the GSTM1 and GSTT1 polymorphisms.②A combined null genotype at GSTM1 and GSTT1 positively correlated with liver cancer occurrence，and it interacted synergistically with hepatocar-cino-genesis.③The risk of HCC between first-degree relatives and probands is not significantly different.