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Aim To investigate the relationship between infections by HBV genotype B or C strains with spontaneous YMDD mutations and the occurrence of hepatocellular cancer in HBV-related liver cirrhosis patients.Materials and Methods At the same period, 264 liver cirrhosis patients not treated with anti-virus drugs, including 81 LC patients with hepatocellular cancer, were included in our study.HBV YMDD mutations were detected by fluorescence hybridization bioprobe PCR and melting curve assay using Diagnosis Kit for HBV YMDD Mutation (Qiagen Biotechnology).Serum HBV genotypes were detected by real time PCR using genotype specific TaqMan probe.According to datas type, t-test, x2-test and unconditional Logistic regression were used for statistical analysis.Results In the hepatocellular cancer group (HCC group), genotype C strains, spontaneous YMDD mutations and genotype C strains with YMDD mutations were detected in 33 patients (40.74％), 13 patients (16.05％) and 11 patients (13.58％), respectively.In the liver cirrhosis group (LC group), HBV genotype C strains, spontaneous YMDD mutations and genotype C strains with YMDD mutations were detected in 33 patients (18.03％), 7 patients (3.83％) and 2 patients (1.09％), respectively.The constituent ratios differences of genotype C strains, spontaneous YMDD mutation and genotype C strains with YMDD mutation between these two groups were statistically significant (x2 =15.441, P =0.000 ; x2 =11.983, P =0.001 ; P =0.000).In the HCC group and LC group, there were 7 patients infected by genotype B strains with YMDD mutations and 13 patients infected by genotype C strains with YMDD mutation.Further research revealed that HCC was occurred in 2 patients infected by genotype B strains with YMDD mutations and 11 patients infected by genotype C strains with YMDD mutations.The difference was statistically significant (P =0.000).Unconditional logistic regression analyses revealed that patients infected by genotype C strains with spontaneous YMDD mutations had 7.775 fold higher risk for the development of HBVorelated HCC than patients infected by other type HBV strains (P =0.013, 95％ CI: 1.540-39.264).Conclusion Infection by genotype C strains with spontaneous YMDD mutations was an independent risk factor for the occurrence of HCC in liver cirrhosis patients and had important clinical value for earlier warning of HCC.