Recurrent hepatitis C causes significant morbidity after liver transplantation. Because immunosuppression is associated with enhanced viral replication, we postulated that clinical recurrence of the disease may be associated with augmented immunosuppression for rejection. In 96 patients with hepatitis C who received liver transplants, we recorded the interval from transplantation to recurrence, the episodes of steroid-resistant rejection (SRR) requiring OKT3, the number of rejection episodes, and the use of OKT3 induction. Recurrence was diagnosed based on elevated transaminases and characteristic histology. Hepatitis C recurred in 43 of 96 patients. Fifteen of 21 patients (71.4%) who previously had SRR hadrecurrence, versus 28 of 75 patients (37.3%) who either had no SRR (72 patients) or had it after recurrence was diagnosed (3 patients) (P <.01). Mean time to recurrence was 127 ± 31 days in the 15 patients who had had SRR versus 246 ± 42 days in the other 28 patients (P = 0.02). Recurrence and number of rejection episodes were clearly associated: 6 of 33 patients (18.2%) with no rejection had recurrence (P<.05), versus 11 of 26 patients (42.3%) with one rejection episode (P<.05) and 26 of 37 (70.2%) with more than 1 episode (P<.05). OKT3 induction was used in 15 patients; 9 of 15 patients had recurrence (ns) at 337 ± 95 days. Of 72 patients who initially received triple immunosuppression, 30 patients had recurrence at 186 ± 25 days (P = 0.05). Nine patients received primary FK506; 4 had recurrence at 68 ± 14 days. SRR requiring OKT3 is associated with a higher incidence and earlier presentation of recurrent hepatitis C. Multiple rejection episodes are also associated with a higher recurrence rate. Induction immunotherapy, by reducing the rate of early rejection, may delay the clinical recurrence of hepatitis C. (Hepatology 1995;21:30-34).