Objective:To investigate the correlation between plexinC1 (PLXNC1) rs2272335 polymorphism and the family clus-tering genetic susceptibility to primary liver cancer (PLC) in Guangxi and the expression of PLXNC1. Methods:Genotype and alleles of rs2272335 were determined in 20 liver cancer family groups (79 cases) and 10 healthy normal control groups (40 cases) in Fusui County through Time of Flight Mass Spectrometer. Immunohistochemistry detected the PLEXNC1 protein expression. Results:For the alleles of PLXNC1 (rs2272335) site, the risk of hepatocellular carcinoma (HCC) for individuals with [C] allele was 4.16-fold (95%CI=0.37-47.3, P=0.032) compared with that for individuals with [T] allele among the members of the healthy normal control group. The fre-quencies of the [C] and [T] alleles were similar in the HCC patients and the core individuals of liver cancer families (P>0.05). For the genotype of the PLXNC1 (rs2272335) site, the differences in frequencies of TT, TC, and CC genotypes were not statistically significant among the PLC patients and the core individuals of the liver cancer families and normal controls. The PLXNC1 protein expression in HCC (3.12±1.12) was higher than in hepatocellular paracancerous tissues (1.54±0.67) and in benign hepatocellular lesions (1.23±0.87) (P<0.05). Conclusion:The [C] allele of PLXNC1 (rs2272335) site might be the risk gene for the occurrence of PLC family clustering in Guangxi. PLXNC1 protein overexpression was closely correlated with PLC oncogenesis.