A total of 481 recipients of blood transfusions who had received 6,295 units of blood were followed for 6–9 months in order to evaluate the relationship between posttransfusion hepatitis (PTH) and transfusion of blood that is positive for antibody to hepatitis B core antigen (anti-HBc). The incidence of non-A, non-B PTH (NANB-PTH) was 11.9% among the 193 recipients who received one or more units of anti-HBc-positive blood compared to only 3.2% of the 288 recipients of only anti-HBc-negative blood (p < 0.001). There was, however, no statistically significant difference in the prevalence of hepatitis B virus or hepatitis B serological response following transfusion of anti-HBc-positive blood compared to anti-HBc negative blood. The relationship of NANB-PTH following receipt of anti-HBc-positive blood and/or blood with an elevated ALT level was studied in a subset of 230 recipients and their 1,549 donors. Donor anti-HBc appeared to be more closely associated with an increased rate of NANB-PTH than an elevated donor ALT level, or with the volume of blood transfused. Donor blood that was anti-HBc-positive and blood with increased ALT activity behaved as independent variables with respect to the development of NANB-PTH. Although only 15% of the units that were anti-HBc-positive were associated with NANB-PTH, calculation of maxi-mal correlated efficacy predicted that exclusion of the 4% of the units that were anti-HBc-positive might have prevented 43% of the cases of NANB-PTH. The authors conclude that screening donors with surrogate tests should be seriously considered because of the serious complications of NANB-PTH.