OBJECTIVE To evaluate the prevalence of antibodies to hepatitis C virus (anti-HCV), their relation to outcome, and the seroconversion rate in patients with post-transfusion non-A, non-B hepatitis. METHODS Retrospective analysis of prospectively collected serum specimens. METHODS A referral-based university hospital. METHODS Sixty-three consecutive patients who developed non-A, non-B post-transfusion hepatitis after open-heart surgery. All patients had follow-up with serial serum testing and clinical evaluation. The mean (+/- SD) duration of follow-up after hepatitis onset was 81 +/- 33 months (range, 13 to 132 months). Seventeen patients recovered after acute-phase illness, whereas 46 developed chronic disease which, in 30 cases, was confirmed histologically. RESULTS Of 32 patients tested before transfusion, 1 (3.1%) had anti-HCV. Fifty-nine (93%) patients were anti-HCV positive during acute-phase hepatitis: Patients with "early" seroconversion (less than 15 days after hepatitis onset) did not differ from those with "late" seroconversion (greater than 60 days after onset) in epidemiologic, clinical, and biochemical features. The rate of anti-HCV positivity during acute-phase illness was not significantly different among patients who recovered (76%) compared with those who developed chronic disease (95%). At 6 to 12 months, patients whose disease resolved had lower antibody activity than those with progressive disease. Further, during long-term follow-up (1 to 9 years), 53% of patients whose disease resolved but only 6.9% of patients who had progressive disease became anti-HCV negative. CONCLUSIONS Hepatitis C virus is the major cause of post-transfusion hepatitis in Italy. The time to anti-HCV seroconversion varies widely after hepatitis onset and is not significantly associated with acute-phase features or outcome of disease.