Enterohepatic recirculation of irinotecan and one of its metabolites, SN-38, has been observed in pharmacokinetic data sets from previous studies. A mathematical model that can incorporate this phenomenon was developed to describe the pharmacokinetics of irinotecan and its metabolites. A total of 32 patients with recurrent malignant glioma were treated with weekly intravenous administration of irinotecan at a dose of 125 mg/m2. Plasma concentrations of irinotecan and its three major metabolites were determined. Pharmacokinetic models were developed and tested for simultaneous fit of parent drug and metabolites, including a recirculation component. Rebound in the plasma concentration suggestive of enterohepatic recirculation at approximately 0.5–1 h post-infusion was observed in most irinotecan plasma concentration profiles, and in some plasma profiles of the SN-38 metabolite. A multi-compartment model containing a recirculation chain was developed to describe this process. The recirculation model was optimal in 22 of the 32 patients compared to the traditional model without the recirculation component. A recirculation chain incorporated in a multi-compartment pharmacokinetic model of irinotecan and its metabolites appears to improve characterization of this drug’s disposition in patients with glioma.