Neoral dosing is traditionally based on cyclosporine (CyA) trough levels (C(0)). Four-h area under the curve (AUC(0-4)) for Neoral in the early posttransplantation period was shown previously to have a better correlation to acute rejection (AR) and CyA nephrotoxicity (CyANT), compared with C(0). An AUC(0-4) range of 4400 to 5500 microg/h per L during the first week was associated with the lowest AR and CyANT. This article describes a prospective study to assess the feasibility, safety, and efficacy of dosing Neoral solely by AUC(0-4) monitoring, regardless of C(0), in the first 3 mo after kidney transplantation. Fifty-nine kidney transplant recipients received Neoral-based triple immunosuppression. AUC(0-4) was measured on days 3, 5, 7, 10, and 14 and weeks 3, 4, 6, and 8, then monthly. Target AUC(0-4) was 4400 to 5500 microg/h per L. Dose was adjusted by percentage difference from target AUC(0-4). Ninety-four percent of AUC were performed on the scheduled day or close to it. No patients had CyANT while AUC(0-4) was in target range. Four patients had reversible CyANT with AUC(0-4) > 5500. Only 1 of 33 patients (3%) who achieved and maintained AUC(0-4) > 4400 by day 3 posttransplantation had AR, whereas 10 of 22 (45%) of those with day 3 to 5 AUC(0-4) < 4400 had AR (P: = 0.0002). In logistic regression analysis, higher early AUC(0-4) was the only significant variable associated with lower serum creatinine at 3 mo. Neoral dose monitoring by AUC(0-4) is a potentially valuable tool for optimizing Neoral immunosuppression. Attainment of a target range of 4400 to 5500 microg/h per L for AUC(0-4) early after transplantation has been demonstrated to reduce significantly the risk of AR and CyANT.