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Reaching target exposure of busulfan-based conditioning prior to hematopoietic stem cell transplantation is vital for favorable therapy outcomes. Yet, a wide inter-patient and inter-occasion variability in busulfan exposure has been reported, especially in children. We aimed to identify factors associated with the variability of busulfan pharmacokinetics in 124 consecutive patients transplanted at the University Children’s Hospital Zurich between October 2010 and February 2020. Clinical data and busulfan plasma levels after twice-daily intravenous administration were analyzed retrospectively by population pharmacokinetic modeling. The volume of distribution correlated with total body water. The elimination rate constant followed an age-dependent maturation function, as previously suggested, and correlated with the levels of serum albumin. Acute lymphoblastic leukemia reduced busulfan clearance by 20%. Clearance significantly decreased by 17% on average from the start to the third day of busulfan administration, in agreement with other studies. An average reduction of 31% was found in patients with hemophagocytic lymphohistiocytosis and X-linked lymphoproliferative disease. In conclusion, we demonstrate that in addition to known factors, underlying disease and serum albumin significantly impact busulfan pharmacokinetics in pediatric patients; yet, substantial unexplained variability in some patients remained. Thus, we consider repeated pharmacokinetic assessment essential to achieve the desired target exposure in twice-daily busulfan administration.