We evaluated the contribution of hepatitis C virus infection to liver disease in patients with sickle cell anemia. Antibody to hepatitis C virus (anti-HCV) by commercial enzyme immunoassay and a second confirmatory assay were assayed in 121 consecutive patients with sickle cell anemia. Anti-HCV was detected in 25 of 121 patients (20.7%). Of patients transfused > 10 units of blood products, 30.3% were anti-HCV seropositive, whereas 8.6% of those patients who transfused < 10 units were seropositive. In 11 of the 121 patients, serum alanine aminotransferase levels were repeatedly elevated. Nine of these 11 patients were anti-HCV seropositive, one was positive for hepatitis B surface antigen, and one was negative for all viral markers. In contrast, of 110 patients with normal serum alanine aminotransferase levels, only 14% were anti-HCV seropositive. In patients with sickle cell anemia, exposure to hepatitis C is common, related to the number of previous transfusions, and the most likely cause of persistently elevated aminotransferase levels.