Early age at cardiac transplantation may favor successful engrafting with minimal chronic immunosuppression. Fifty-two newborns underwent orthotopic heart transplantation; 47 (90%) survived the operation, and 44 (85%) were late survivors. Actuarial survival was 92% at 1 month, 86% at 1 year, and 84% at 5 years. Forty-four infants who survived 12 weeks and the corresponding 100 rejection episodes were analyzed. Mean follow-up was 2.2 years. The mean number of rejections per year of follow-up was 1.2. No episodes of rejection were identified in six patients. Seven patients had a late rejection episode more than 1 year after transplantation, and only one had a late rejection episode after 2 years. Neonatal cardiac transplantation is effective and durable therapy for uncorrectable heart disease. Intermediate-term results are excellent. Severe rejection is uncommon, and few episodes occur after 1 year of follow-up.