Renal transplant patients commonly receive triple-drug immunosuppression with standardized doses of cyclosporine, azathioprine, and methylprednisolone. Although cyclosporine may decrease the clearance of oral prednisone, data are lacking for methylprednisolone, a glucocorticoid commonly prescribed via a standardized protocol for intravenous therapy and during periods of acute rejection. The disposition of methylprednisolone (doses: 10–60 mg/day) was examined in nine renal transplant patients during the post-transplant period (0.8–14 months). Plasma samples were collected over 24 hr and analyzed for methylprednisolone via HPLC. Pharmacokinetic parameters were determined by non-compartmental analysis. The mean total clearance of methylprednisolone was 379 ml/hr/kg (range 105–672) and the volume of distribution was 1.4±0.5 L/kg. The mean plasma half-life was 2.7±1.1 hr. When normalized to a 1 mg dose of methylprednisolone, the mean peak concentration at 1 hr was 10.0±3.5 ng/ml with an 8 hr concentration ranging from 0.3 to 5.5 ng/ml. An appreciable variability in methylprednisolone metabolism thus exists in renal transplant recipients receiving tri ple-drug immunosuppression. This may partially ex plain the variable response to steroid therapy during acute rejection episodes and chronic immunosuppression as well as the unpredictable occurrence of chronic steroid toxicity.