BACKGROUND Despite the various immunosuppressive regimens presently in use, acute rejection in the early postoperative period continues to occur in 20 to 40% of renal transplant patients. In a double-blind, multicentred study, we investigated the ability of two different doses of sirolimus (rapamycin, RAPAMUNE), a new class of immunosuppressant that blocks cell cycle progression, to prevent acute rejection in recipients of primary mismatched renal allografts when added to a regimen of cyclosporine (cyclosporin A, CsA) and corticosteroids. METHODS Between October 1996 and September 1997, 576 recipients of primary mismatched cadaveric or living donor renal allografts were randomly assigned in a 2:2:1 ratio (before the transplant operation) to receive an initial loading dose of either 6 or 15 mg of orally administered sirolimus, followed by a daily dose of either 2 or 5 mg/day, or to receive a matched placebo. All groups received cyclosporine (microemulsion formula, CsA) and corticosteroids. The primary endpoint was a composite of first occurrence of biopsy-confirmed acute rejection, graft loss, or death during the first 6 months after transplantation. Safety data were monitored by an independent drug safety monitoring board. RESULTS Based on an intention-to-treat analysis of 576 patients, there were no significant differences in patient demographic or baseline characteristics among treatment groups. The overall rate of the primary composite endpoint for the 6-month period after transplantation was 30.0% (68/227) in the 2 mg/day sirolimus group and 25.6% (56/219) in the 5 mg/day sirolimus group, significantly lower than the 47.7% (62/130) in the placebo group (P=0.002, P<0.001, respectively). During this period, the incidence of biopsy-confirmed acute rejection was 24.7% (56/227) in the 2 mg/day sirolimus group and 19.2% (42/219) in the 5 mg/day sirolimus group, compared with 41.5% (54/130) in the placebo group (P=0.003, P<0.001, respectively), representing a significant reduction in acute rejection of 40.5 and 53.7%, respectively. The need for antibody therapy to treat the first episode of biopsy-confirmed acute rejection was significantly reduced in the 5 mg/ day sirolimus group (3.2%) compared to the placebo group (8.5%; P=0.044). The results 1 year after transplantation were similar for the efficacy parameters studied. Adverse events and infections occurred in all groups. CONCLUSIONS The addition of either 2 mg/day sirolimus or 5 mg/day sirolimus to CsA/corticosteroid therapy significantly reduces the incidence of acute rejection episodes in primary mismatched renal allograft recipients, without an increase in immunosuppressant-related side effects, including infections and malignancy, at 6 months and at 1 year after transplantation.