Several reports suggest that posttransfusion hepatitis C causes more aggressive histological activity than disease that is acquired via other routes. We sought to determine whether mode of transmission affects disease outcome. We studied the demographics, presenting laboratory data, and clinical course of 627 consecutively evaluated nonalcoholic patients with chronic hepatitis C. Two hundred eighty-two patients (45%) were transfusion recipients, 262 (42%) acquired the disease via other routes of percutaneous exposure, and 83 (13%) were without risks. Liver histology was available in 463 patients (215 transfusion recipients, 195 non-transfusion recipients, and 53 who were were without risks) and showed noncirrhosis in 274 (59%), cirrhosis in 173 (37%), and hepatocellular carcinoma in 16 patients (4%) who also had underlying cirrhosis. Duration of follow-up was 1 to 25 years (mean, 48 months; median, 21 years). One hundred eighteen of 173 (68%) cirrhotic patients were transfusion recipients; 40 of 173 (23%) cirrhotic patients acquired infection via other percutaneous exposure, and the remainder were without known risk factors (P < .001). Among the 215 patients with blood transfusions for whom histology was available, 118 of 215 (55%) had cirrhosis and 89 of 215 (41%) were noncirrhotic (P < .001); 8 transfused patients (4%) had hepatocellular carcinoma. In the percutaneous group, 40 of 195 (21%) of the patients were cirrhotic versus 153 of 195 (78%) who were noncirrhotic (P < .001); 2 patients (1%) had hepatocellular carcinoma. During the follow-up period, 59 of 189 (31%) of the cirrhotic patients (including those 16 individuals with hepatocellular carcinoma) developed hepatic decompensation. By univariate analysis, the risk of liver failure was related to age at viral acquisition, but by logistic regression analysis, only mode of transmission, and not age or estimated disease duration, predicted risk of liver failure. Patients with posttransfusion hepatitis C were more likely to develop decompensation than individuals who were not transfusion recipients (relative risk, 3.921; CI = 2.205 to 7.015). Serum albumin, prothrombin time, and platelet count at presentation were independent laboratory predictors of subsequent hepatic decompensation. The rate of hepatocellular carcinoma development among all cirrhotic patients during the follow-up period was 1.2% per year. Patients with posttransfusion hepatitis C are at greater risk of cirrhotic decompensation than those individuals with non-transfusion-acquired disease. The risk of liver failure is more closely related to the mode of transmission than to age at viral acquisition or to the duration of infection.