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Non-adherence to a prescribed immunosuppressive regimen increases risk for late allograft rejection (LAR). We implemented a protocol for immunosuppression management which decreased variation in calcineurin inhibitor blood levels in pediatric liver transplant recipients by controlling for confounders such as physician practice variability. We hypothesized that patients with increased variation in tacrolimus blood levels despite implementation of the immunosuppression management protocol were at increased risk for LAR. We conducted a single center retrospective cohort study of 101 pediatric liver transplant recipients who were at least one year post liver transplantation and receiving tacrolimus for immunosuppression. The primary outcome variable was biopsy proven allograft rejection. Primary candidate predictor variables were the standard deviation (SD) of tacrolimus blood levels (a marker of drug level variability), mean tacrolimus blood level, age, and insurance type. SD of tacrolimus blood levels was determined for each patient from a minimum of four outpatient levels during the study period. Unadjusted and adjusted logistic regression models were used to determine the prognostic value of candidate predictors. The median and interquartile range of the SD of tacrolimus blood levels was 1.6 (1.1, 2.1). Eleven episodes of LAR occurred during the study period. Ten of the 11 episodes occurred in patients with tacrolimus blood level SD > 2. Insurance type, mean tacrolimus blood level and SD of tacrolimus blood levels were significantly related to LAR in the unadjusted analyses (p<0.05). A multivariable model including age, insurance type, mean and SD of tacrolimus blood levels was significantly associated with LAR (validated C-statistic = 0.88, p = 0.012). The adjusted odds of rejection for a one unit increase in the SD of tacrolimus blood level was 3.49 (95% CI 1.31 to 9.29). Effects of age and insurance status on LAR did not provide independent prognostic value after controlling for SD. Variation in tacrolimus blood levels is associated with an increased risk of LAR in pediatric liver transplant recipients. Despite standardized management of tacrolimus levels to control for confounders, some patients were found to have significant variability of tacrolimus blood levels. This may be due to non-adherence and amenable to targeted psychosocial and behavioral interventions to prevent LAR.