Background: Cyclosporine exposure, as estimated by the area under the curve (AUC), predicts outcomes in renal transplantation. Cyclosporine concentration at two h post-dose (C2) has been shown to be the most reliable, single-point surrogate marker for AUC. The objective of this study was to measure renal function beyond month 2 post-transplant using two different C2 maintenance targets in combination with enteric-coated mycophenolate sodium (EC-MPS), corticosteroids, and basiliximab induction. Methods: In this open-label, multicenter trial, renal transplant recipients entered one of two randomized groups at day 61 post-transplant: group A (higher-C2 range) or group B (lower-C2 range). Results: Patients (164) were recruited, and 141 patients were entered the randomized groups (group A, n = 66; group B, n = 75). At 12 months, the mean calculated creatinine clearance was significantly greater in group B than in group A (79.2 vs. 71.0 mL/min, p < 0.05). Biopsy-proven acute rejection occurred in 14.7% patients in group B and in 24.2% patients in group A (n.s.). During the 12-month trial, 17.7% patients discontinued EC-MPS because of adverse events. Group B (44.0%) had fewer serious adverse events when compared with group A (62.1%; p = 0.04). Overall patient and graft survival were 99.4% and 95.7% respectively. Among 99 high-risk patients (i.e., African-American race, previous transplant, PRA >35% or >4 HLA mismatches), mean creatinine clearance at 12 months was 65.6 mL/min and biopsy-proven rejection occurred in 20.2% patients. Conclusions: Low cyclosporine C2 levels are associated with improved renal function compared with higher C2 levels when used in conjunction with EC-MPS, steroids and basiliximab induction. EC-MPS with low cyclosporine C2 levels, corticosteroids and basiliximab provides excellent renal function with good efficacy even in high-risk patients. © 2007 Blackwell Munksgaard.