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The prevalence of pulmonary methicillin-resistant Staphylococcus aureus infections in patients with cystic fibrosis (CF) has increased over the last 2 decades. Two concentrations-a postdistributive and a trough-are currently used to estimate the area under the curve (AUC) of vancomycin, an antibiotic routinely used to treat these infections, to achieve the target AUC/minimum inhibitory concentration of ≥400 mg·h/L in ensuring optimal dosing of this drug. This study evaluated precision and bias in estimating vancomycin AUCs obtained either from a population pharmacokinetic (PK) model by using a single trough concentration or from standard PK equation-based 2-point monitoring approach. AUCs were either obtained from a single trough concentration-fitted model or derived from a model fitted by 2 concentration points. Children ≥2 years of age with CF received intravenous vancomycin at 2 centers from June 2012 to December 2014. A population PK model was developed in Pmetrics to quantify the between-subject variability in vancomycin PK parameters, define the sources of PK variability, and leverage information from the population to improve individual AUC estimates. Twenty-three children with CF received 27 courses of vancomycin. The median age was 12.3 (interquartile range [IQR] 8.5-16.6) years. From the individual vancomycin PK parameter estimates from the population PK model, median AUC was 622 (IQR 529-680) mg·h/L. Values were not significantly different from the AUC calculated using the standard PK equation-based approach (median 616 [IQR 540-663] mg·h/L) (P = .89). A standard PK equation-based approach using 2 concentrations and a population PK model-based approach using a single trough concentration yielded unbiased and precise AUC estimates. Findings suggest that options exist to implement AUC-based pediatric vancomycin dosing in patients with CF. The findings of this study reveal that several excellent options exist for centers to implement AUC-based pediatric vancomycin dosing for patients with CF., (© 2018, The American College of Clinical Pharmacology.)