Interleukin (IL)-12 plays an essential role in host defense against infectious diseases. Serum IL-12 concentration and blood mononuclear cell production with or without specific interferon (IFN)-gamma priming were investigated in 65 chronic hepatitis C virus (HCV) patients and 25 healthy donors. HCV patients had higher serum IL-12 levels (P = .004) and produced higher amounts after IFN-gamma priming (P < .001) than donors. A subset of patients did not produce IL-12: They had lower serum levels (P = .032) and showed signs of liver piecemeal necrosis less frequently (P = .011). Patients with greater liver necroinflammatory activity produced more IL-12 than patients with minimal or mild activity and donors (P < .01). During IFN-alpha therapy for 16 HCV patients, individuals with end-of-treatment alanine aminotransferase normalization and clearance of viremia had higher serum levels and produced more IL-12 than those who did not (P < .05). These results suggest a role for IL-12 in the immunopathogenesis and outcome of HCV infection.