Background. Patients with chronic liver disease (CLD) have extrahepatic manifestations and impaired health-related quality of life (HRQOL), and hepatitis C virus (HCV) infection is a leading cause of CLD, cirrhosis, and hepatocellular carcinoma (HCC). This study is aimed at assessing HRQOL in patients with HCV infection in the rural areas and identifying factors associated with impairment of HRQOL. Methods. A cross-sectional study was conducted in a county of Liaoning Province in northeast China. HRQOL of patients with HCV infection was assessed using the chronic liver disease questionnaire (CLDQ) and EuroQol-5 dimensions (EQ-5D). Data were transformed to score comparisons of six major CLDQ domains, EQ index, and visual analog scale (VAS). Results. A total of 397 (93.4%) subjects, including 67 healthy subjects (HSs), 314 patients with chronic hepatitis C (CHC), and 16 patients with liver cirrhosis (LC) completed the study. The overall quartile CLDQ scores for HSs, patients with CHC, and patients with LC were 6.4 (6.0, 6.7), 5.8 (4.6, 6.4), and 4.1 (3.0, 6.0), respectively. The quartile scores of EQ index for the three groups were 1.0 (1.0, 1.0), 1.0 (0.8, 1.0), and 0.9 (0.6, 1.0), respectively. The median scores of EQ VAS for the three groups were 85.0, 60.0, and 60.0, respectively. Female sex, patients with family history of hepatitis, other comorbid chronic diseases, drinking, and disease duration≥10 years were associated with significant improvement in overall CLDQ scores, and family history of hepatitis and other comorbid chronic diseases were considered predictive factors for EQ index and VAS, respectively. Conclusions. Compared with HSs, HCV infection had a greater negative impact on HRQOL in patients with CHC and LC. The significant factors associated with HRQOL include female sex, patients with a family history of hepatitis, other comorbid chronic diseases, drinking, and disease duration≥10 years. Patients with HCV infection in the rural areas should be paid careful attention regarding their HRQOL with proper health education and disease management.