BACKGROUND: Mycophenolate mofetil (MMF), compared to azathioprine (AZA), reduces acute rejection and treatment failure in cyclosporine (CsA) and steroid regimens, but its effect on graft survival is unproven from prospective studies and prolonged use is costly. This study evaluated the efficacy and tolerability of replacing MMF by AZA after 3 months. METHODS: This 28 center, prospective, 12-month, parallel group, open-label study, randomized patients to three groups with microemulsion formulation of CsA (ME-CsA) and steroids as baseline therapy. Group 1 (n=158) received MMF for 3 months, replaced by AZA for 9 months; group 2 (n=162) received MMF for 12 months; and group 3 (n=157) received AZA for 12 months. RESULTS: Treatment failure and the cumulative rate of acute rejection were significantly lower in the MMF groups compared with the AZA group (P=0.007 and P=0.03, respectively). Graft loss, death, and safety profiles of all three treatments were similar over 12 months, as were mean serum creatinine levels. Switching from MMF to AZA did not affect treatment failure. No patient in group 1 experienced a recurrent rejection after month 3, one patient died, and nine patients experienced first rejection episodes. Most rejections (6/9) were steroid-sensitive and histologically mild. CONCLUSIONS: Replacement of MMF by AZA after 3 months of therapy with ME-CsA and steroids provides comparable efficacy and safety profiles to continuous MMF over 12 months. Although apparently a cost-effective option, long-term studies are required to assess the benefit/risk ratio of this therapy switch in different patient subpopulations.