In cyclosporine-based protocols, everolimus is more effective than azathioprine to reduce acute rejection. Ketoconazole may reduce cyclosporine and everolimus requirements. We compared kidney transplant patients treated with everolimus or azathioprine in a ketoconazole- and cyclosporine-based immunosuppressive regimen. This open-label, prospective trial of low immunologic risk patients. Included one group (n 11) who received everolimus (target blood level, 3–8 ng/mL) and the other (n 11) azathioprine (2.0 –2.5 mg/kg/d). Both received steroids, ketoconazole, and cyclosporine with C0 targets (ng/mL) in the everolimus group of 200–250, 100–125, and 50–65 for months 1 and 2 and thereafter and in the azathioprine group of 250–300 in month 1, 200–250 in month 2, 180–200 until month 6, and 100–125 thereafter. Their baseline characteristics were similar. Two biopsy-proven acute rejections occurred in each group. Three-year graft and patient survival in both groups was 100%. Creatinine clearances at months 6, 12, 24, and 36 were 63.7 25.4, 58.9 24.9, 56.0 22.9, and 57.0 27.6 in the everolimus group versus 72.6 20, 68.6 21.3, 71.4 23.2, and 68.4 19.2 in the azathioprine group (NS for every comparison). Major complications were rare and similar in both groups. Five patients in the everolimus group received simvastatin versus 4 in the azathioprine cohort (P .53). The average cyclosporine doses to achieve targets were 0.8 –1.2 mg/kg in the everolimus group and 1.6 –2.2 mg/kg in the azathioprine group. The average everolimus dose after month 2 was 0.75– 0.9 mg/d. We concluded that with cyclosporine, ketoconazole, and steroids, everolimus was as effective and safe as azathioprine. Cyclosporine reduction with everolimus did not influence graft survival or function at 3 years.