With the increasing success of liver transplantation and the proven effectiveness of highly active retroviral therapy in HIV-positive patients, liver transplantation has been performed successfully in selected HIV-positive recipients with CD4 and an HIV viral load response to highly active antiretroviral therapy. In these patients, an interaction between a protease inhibitor (nelfinavir) and tacrolimus has been shown. The effect of nelfinavir on the pharmacokinetics of sirolimus, a newer immunosuppressive drug, is currently not known. The goal of the present case report is to document the interaction between sirolimus and nelfinavir in a liver transplantation patient. A 40-year-old woman who was HIV positive underwent a cadaveric liver transplantation for acute fulminant liver failure secondary to nevirapine (a nonnucleoside reverse transcriptase inhibitor). Postoperatively, she was treated with tacrolimus and steroids. She experienced steroid-resistant rejection and was started on sirolimus on the 17th postoperative day. Kinetic parameters were determined after a 2-mg oral dose of sirolimus and 250 mg of nelfinavir by collecting multiple peripheral venous blood samples before and after sirolimus administration. The kinetic parameters were compared with parameters from three liver transplantation patients on sirolimus who were not on nelfinavir. After normalizing the kinetic parameters to sirolimus dose of 1 mg/d, 0-hour and 24-hour trough sirolimus concentrations were nine-fold and five-fold higher for the patient who was on nelfinavir, compared with those who were not on nelfinavir. The maximum concentration was 3.2 times higher, the area under the concentration curve was 1.6 times higher, and the terminal disposition half-life was prolonged by 60%. The time to reach the peak concentration was 1 hour in all patients. Increase in trough concentration, peak concentration area under the curve concentration, and prolongation of half-life of sirolimus has been shown in a patient who was on a low dose (one fifth the recommended dose) of nelfinavir.