In 11 European centers, first cadaveric renal allograft recipients were randomized to CsA (n = 42) or sirolimus (n = 41). Dosing of these agents was concentration-controlled and open-labeled. All patients received corticosteroids and azathioprine. At 12 months, graft survival (98% sirolimus vs 93% CsA), patient survival (100% vs 98%), and incidence of biopsy-confirmed acute rejection (41% vs 38%) were similar. Serum creatinine was lower with sirolimus, significantly (P </=.05) so at 3 and 4 months, and serum uric acid and magnesium were normal. Laboratory abnormalities were reported significantly more often with sirolimus, which included hypertriglyceridemia (51% vs 12%), hypercholesterolemia (44% vs 14%), thrombocytopenia (37% vs 0%), leukopenia (39% vs 14%), and, of lesser importance, increased liver enzymes and hypokalemia. These abnormalities improved 2 months after transplantation when the sirolimus target trough level was lowered from 30 to 15 ng/mL. Occurrence of cytomegalovirus was comparable (14% vs 12%), but incidence of herpes simplex (24% vs 10%, P =.08) and pneumonia (17% vs 2%, P =.03) were higher with sirolimus. No gingival hyperplasia was seen with sirolimus, tremor was rare, and hypertension was less frequent (17% vs 33%). Two malignancies were observed with CsA, none with sirolimus. Results at 12 months suggest that sirolimus can be used as base therapy in the prophylaxis of acute renal transplant rejection, and has a safety profile that differs from that of CsA.