Allograft rejection remains a major cause of morbidity and mortality. Cyclophosphamide, a nitrogen mustard, is a potent immunosuppressive agent with effects on both T- and B-lymphocytes, and thus may be effective in preventing further cellular and/or humoral rejection in cardiac transplant recipients with recurrent or recalcitrant rejection. We retrospectively reviewed the records of 320 surviving cardiac transplant recipients. Cyclophosphamide was substituted for azathioprine in 28 patients because of frequent allograft rejection. We then reviewed the rejection history of these 28 patients, specifically looking at rejection frequency, type (cellular, vascular or mixed), and treatment. Cyclophosphamide was substituted for azathioprine at an average of 8.4 +/- 2.8 months after transplantation. Despite a 56.0% reduction in prednisone dose (p < 0.001), at least a threefold reduction in rejection frequency (p < 0.001) was observed, while cyclosporine levels were unchanged. Twenty-eight percent of the patients did not experience even mild rejection after beginning therapy with cyclophosphamide, 55% had 1 or 2 subsequent mild or moderate rejection episodes, and only 17% had more than two subsequent episodes of mild or moderate rejection. Overall, the number of treated rejection episodes decreased from 0.37 episodes per patient month with azathioprine to 0.10 episodes per patient month on therapy with cyclophosphamide. Separating the patients into two groups based on the predominant rejection type (cellular vs. vascular) occurring at the time of cyclophosphamide substitution revealed a similar reduction in cellular and vascular rejection in each respective group. While white blood cell count decreased by 16%, cyclophosphamide was not discontinued in any patient due to leukopenia, and no change was noted in hematocrit. Cyclophosphamide appears to be safe and effective in maintenance immunosuppression and may reduce rejection frequency in some patients with frequently occurring allograft rejection without necessitating the augmentation of either corticosteroids or cyclosporine.