We evaluated the efficacy of the addition of the lymphoblasticidal agent vincristine to standard immunosuppression in heart transplantation in a prospective randomized study of 92 patients (46 to receive and 46 to not receive vincristine) with a follow-up period of 12 months. Patients received either equine antithymocyte globulin for the first week or OKT3 monoclonal antibody (OKT3) for the first 10 or 14 days after transplantation. Six to eight doses of vincristine were given over 9-12 weeks, beginning 2 days after completion of ATG or OKT3. The number of rejection episodes in the first six months posttransplantation, the percentage of patients corticosteroid maintenance-free at one year, cumulative immunosuppressive drug doses, deaths, infections, and neuropathy were followed. The addition of vincristine resulted in more patients achieving corticosteroid maintenance-free status at one year (vincristine 68%, no vincristine 38%, P = 0.01). In comparing patients at relatively high risk for rejection (those younger than 55 years and all females) with those at relatively low risk (males older than 55 years), only the high-risk vincristine-treated patients showed significantly fewer rejection episodes and a higher corticosteroid maintenance status at one year (66% vs. 32%, P = 0.01). There were no significant differences in survival (vincristine 96%, no vincristine 98%), infection, or amounts of other immunosuppressive agents used. The major side effect was neuropathy, which occurred more frequently in the vincristine-treated group (43% vs. 18%, P less than .001). We conclude that vincristine acts as an immunosuppressive agent in cardiac transplantation, particularly in patients at higher risk for rejection.