Although newer immunosuppressive drugs control acute rejection better and have short-term economic advantages, their long-term cost-effectiveness is unknown. We studied the frequency with which different maintenance immunosuppression regimens were used in 3 renal transplantation cohorts treated in 1990, 1994, and 1998 (total number, 3279). We calculated the mean annual immunosuppressive costs based on the true costs in a medium-sized hospital. Cyclosporine, with or without azathioprine, was used almost exclusively as the initial maintenance immunosuppressive therapy in 1990-1994. In 1998, 65% of patients received mycophenolate mofetil (MMF), and 20% received tacrolimus (Tac). A growing number of patients from 1990-1994 were converted to MMF (12%-17%) and Tac (4%-8%), while treatment of those from the 1998 cohort remained stable. According to year 2000 costs, the mean immunosuppressive cost at 1 year in 1998 (5380 euros) was almost twice that of 1994 (2902 euros) or 1990 (2855 euros). In these 2 groups the mean cost was stable until 1996, then increased faster in the 1994 cohort (24.8%) than in the 1990 cohort (17.3%), although it remained significantly lower than that in 1998. Correction of the evolution of drug prices and the purchasing value of the peseta greatly absorbed these changes. The MMF and Tac regimens showed greater mean graft life, but without reaching statistical significance in a multivariate study. The introduction of new immunosuppressive drugs has had an important economic effect since 1996; its cost-effectiveness is still pending confirmation in Spain.