Background Acute pulmonary allograft rejection (AR) is the most important risk factor for bronchiolitis obliterans syndrome (BOS), which is associated with reduced quality of life and decreased survival after lung transplantation (LTx). Trough (C0) cyclosporine (CyA) levels have a poor correlation with area-under-the-curve (AUC) measurements of cyclosporine exposure compared with 2-hour post-dose (C2) levels, but there are no published guidelines for C2 levels after LTx. Hence, we assessed the utility of C2 target levels to prevent AR. Methods Fifty consecutive de novo LTx patients (bilateral, 44; single, 3; heart–lung, 3; cystic fibrosis, 20; non–cystic fibrosis, 30) managed with CyA were assigned target C2 levels as follows: >800 μg/liter within 48 hours; >1,200 μg/liter from Week 1 to Month 1; >1,000 μg/liter in Month 2; >800 μg/liter in Month 3; >700 in μg/liter in Months 3 to 6; and >600 μg/liter thereafter. Surveillance transbronchial biopsies (TBBxs) were performed at 3, 6, 9 and 12 weeks. An intention-to-treat analysis was performed and results compared with our historic controls managed by C0 monitoring. Results Fifteen of 50 (30%) LTx recipients developed AR on 23 of 171 TBBxs (Grade A2:A3 = 21:2) during follow-up (mean ± SD) of 1,185 ± 426 days (range, 16 to 1,790 days). Eighteen of 23 AR episodes occurred after sub-target C2 levels. The 30-day, 1-, 3- and 5-year actuarial survival rates were 98%, 94%, 82% and 77%, respectively. Thirteen of 48 (27%) evaluable LTx recipients developed BOS with 1-, 3- and 5-year freedom-from-BOS rates of 96%, 79% and 59%, respectively. Only 1 patient developed severe renal dysfunction. Conclusions Achieving and maintaining target C2 levels after LTx is associated with reduced rates of AR and BOS, preservation of renal function, and excellent short-term survival rates when compared with historic controls. J Heart Lung Transplant.