To evaluate the effectiveness of immune serum globulin (ISG) in preventing non-A, non-B hepatitis, 291 heart surgery patients who received blood from voluntary donors were randomly assigned to receive either ISG or no additional protection. ISG was given intramuscularly before and 1 week after transfusion. 98 controls and 100 in the ISG group completed the study. Post-transfusion non-A, non-B hepatitis developed in 11 (11.2%) controls but in only 3 (3.0%) of the ISG group (p = 0.0203). 8 (72.7%) of control group with hepatitis had symptoms, and in 5 (45.4%) the disease became chronic. The disease was self-limiting in all 3 ISG patients affected, and only 1 of them had symptoms. Among those with non-A, non-B hepatitis aminotransferase levels were higher in the controls than in the ISG patients. Incubation periods longer than 8 weeks correlated with a tendency for the disease to become chronic. ISG recipients had shorter as well as more homogeneous incubation periods. ISG could be a safe, low-cost means for preventing post-transfusion non-A, non-B hepatitis which does not call for the discarding of donated blood.