Background. Hepatitis B virus (HBV) preS mutations are frequently isolated from patients with severe forms of liver disease. Meanwhile, genotype C has been shown to cause more serious liver disease than genotype B. This study assesses the frequency of preS mutation in Chinese patients with genotype C chronic HBV infection and its relation to liver damage. Methods. Seventy-nine persistently infected patients (25 asymptomatic carriers, 28 with chronic hepatitis, and 26 with hepatocellular carcinoma) with genotype C HBV were analyzed. Levels of HBV DNA, hepatitis B e antigen (HBeAg), alanine aminotransferase, and aspartate transaminase and mutations in the preS region were determined. Results. The correlations of preS deletion with disease progression were distinct: preS deletion mutations were more commonly found in the hepatocellular carcinoma (HCC) group than in the chronic hepatitis B (CHB) or asymptomatic carrier (ASC) groups, with the frequencies of 38.46% (10/26) in the HCC, 7.14% (2/28) in the CHB, and 4.00% (1/25) in the ASC (P = 0.001) groups. The HBeAg-positive rate and HBV DNA levels were comparable between patients with the preS mutation and those without. Conclusions. PreS deletion mutations of genotype C HBV might play a role in HBV-related hepatocarcinogenesis.