Mycophenolate mofetil (MMF) is an immunosuppressant routinely used in allogeneic hematopoietic cell transplantation (alloHCT) to promote stem cell engraftment and prevent acute graft vs host disease. Administered as a prodrug, MMF is converted by esterases to the active moiety, mycophenolic acid (MPA). The impact of clinical covariates on unbound MPA exposure was investigated with a population pharmacokinetic approach. Pharmacokinetic data were obtained from routine area under the curve (AUC) monitoring of unbound MPA drug levels in 36 pediatric (n = 31) and young adult (n = 5) patients undergoing alloHCT for a variety of malignant and nonmalignant disorders. Unbound MPA pharmacokinetics were well described by a 2-compartment model with linear elimination and first-order absorption. The important clinical covariates affecting unbound MPA pharmacokinetics were weight, estimated creatinine clearance, and total bilirubin. Unbound MPA clearance was reduced, and exposure (AUC(0-8)) increased in individuals with decreased renal function. In individuals with severe hepatic dysfunction (total bilirubin >10 mg/dL) unbound MPA clearance was approximately 3-fold lower compared with patients with normal to mild hepatic impairment. In alloHCT recipients with renal dysfunction or severe hepatic injury, dose reductions may be necessary to prevent toxicity and ensure optimal immunosuppression.