Routine screening of blood donors for anti-hepatitis C virus (HCV) has been implemented in most developed countries. However, the independent efficacy of such screening has not been established in a controlled, prospective study. We tracked 478 patients transfused with anti-HCV-negative blood by first-generation enzymelinked immunoassay (ELA) between July 1989 and May 1990 and compared the incidence of transfusion-associated hepatitis and HCV infections with that found among 280 patients transfused with blood unscreened for anti-HCV during the immediately preceding year. Of the 280 patients who had received transfusions before donors were screened for anti-HCV, 27 (9.6%) developed posttransfusion hepatitis and 1 additional patient seroconverted to anti-HCV without evidence of hepatitis, for a risk of posttransfusion HCV infection of 10.7% (28 of 262 recipients seronegative for anti-HCV before transfusion). Ofthe 478 patients transfused after July 1989 with blood screened for anti-HCV, only 9 (1.9%) developed posttransfusion hepatitis for a risk reduction of 80%. Seven of the 9 residual cases of hepatitis were caused by HCV (7 of 456 recipients seronegative before transfusion or 1.5%) for a risk reduction of transfusion-associated HCV infection of 86%. In retrospect, an anti-HCV positive donor was detected by second-generation im- munoassay in 4 (57%) of the 7 HCV cases from the study cohort and in 19 of the 23 (83%) cases from whom all Abbreviations: HCV, hepatis C virus; EM, enzyme-linked immunoassay; anti-HBc, antibodies to hepatitis B core antigen; ALT, alanine transaminase; HBsAG, hepatitis B surface antigen; RIBA, recombinant immunoblot assay; ELISA, enzyme-linked immunosorbent assay; Ig, immunoglobulin.