Sirolimus is a new immunosuppressive agent that lacks the nephrotoxicity and neurotoxicity associated with calcineurin inhibitors. The addition of sirolimus to immunosuppressive protocols may thus allow sparing of calcineurin inhibitors and reduction or elimination of associated toxicities. Between January 2000 and July 2001, sirolimus was administered to 55 of 116 consecutive liver recipients. The remaining 61 patients served as the comparison group in the retrospective analysis. In the sirolimus group, perioperative steroids were reduced, and calcineurin inhibitor initiation was delayed. All infectious episodes that occurred within 60 days of liver transplantation were evaluated but were limited to 1 per patient for statistical analysis of sepsis. Demographic variables were comparable between groups. Patients receiving sirolimus experienced more infection (47.2% vs. 18.03%, P<0.001), and this effect persisted across high and low dosage ranges and sirolimus levels. A trend toward increased length of stay was noted (P=0.07). No difference between groups was found in acute rejection rates (17.5% vs. 22.5%), 1-year graft (81% vs. 89%), patient survival (86% vs. 89%), or hepatic artery thrombosis. In conclusion, despite reduction of other immunosuppressants, patients receiving even low doses of sirolimus experienced increased sepsis rates. This agent may have greater usefulness for patients with threatened renal function or patients with chronic rejection after wound healing has occurred.