In 1983, anticipating the introduction of alanine aminotransferase (ALT) screening to limit the frequency of transfusion-associated non-A, non-B hepatitis, we evaluated 100 consecutive blood donors with elevated ALT levels. To assess the role of hepatitis C virus (HCV) in blood donors with ALT elevations, we tested donor sera for antibody to HCV (anti-HCV). Antibody was detected and "confirmed" by a second-generation recombinant immunoblot assay (RIBA-2) in 17% of donors. Aminotransferase levels were higher in donors with anti-HCV. Antibody to HCV was more frequent in donors with persistent ALT elevations and in those who used intravenous drugs; anti-HCV was less frequent in donors who were overweight, who drank alcohol regularly, and who had no alternative explanation for an elevated ALT level. We conclude that asymptomatic ALT elevations are infrequently associated with HCV infection, unless the elevation is substantial, persistent, or associated with intravenous drug use. Hepatitis C virus infection is an unlikely cause of asymptomatic ALT elevations in persons who drink alcohol regularly or who are obese; however, HCV infection is a more likely cause of ALT elevations in thin persons who do not drink alcohol regularly.