Primary nonfunction following orthotopic liver transplantation is characterized by rapidly rising serum transaminases, minimal bile production, and severe coagulopathy, which can progress to hypoglycemia, hepatic encephalopathy, and acute renal failure. Untreated it has a mortality of over 80% and to date the only treatment has been retransplantation. As a result of the beneficial effect of Prostaglandin infusion in patients with fulminant hepatic failure, this trial was conducted to determine whether PGE1 would be of value in primary nonfunction. We have encountered 16 cases of primary nonfunction in 94 liver transplants, an incidence of 17%. Initially in the program, there were 6 occurrences of nonfunction that did not receive PGEi; 3 underwent retransplantation (2 survivors), 2 died awaiting another liver, and in one recovery of hepatocellular function occurred with supportive care but the patient died of cytomegalovirus infection. Ten patients received PGE1 within 4—34 hr of transplantation. Within 12 hr of treatment, 8 patients responded with a significant fall in the AST (129 U/hr) whereas, in the untreated group, the AST continued to rise (267±102 U/hr) at the same rate as prediagnosis (337±95 U/hr). At the conclusion of the infusion (4—7 days) in the 8 responders, there were significant decreases in AST (4386±546 U/L to 102±21 U/L), prothrombin time (22± 2 to 12±.4 sec) and partial thromboplastin time (4 5 ± 3 - 2 9± 4 sec), and significant increases in coagulation factor V (26±8 to 95±12%) and factor VII (10±5 to 61± 4%). No serious side effects occurred, although 2 patients developed diarrhea, and abdominal cramps. Two patients treated with PGEX were retransplanted at 1 0 - 36 hr and were considered nonresponders. Graft survival was 80% in the PGEi-treated group and 17% in the untreated group (P<0.05) and patient survival was 90% and 33%, respectively. This study suggests a potential benefit of PGEi in the treatment of primary nonfunction.