Multiple-compartment disposition of insulin has been demonstrated following intravenous administration; however, because of slow absorption and flip-flop kinetics, meal-time insulin pharmacokinetics have been described by a 1-compartment model. Technosphere insulin (TI) is an inhaled human insulin with rapid absorption and a distinct second compartment in its pharmacokinetics. The aim of this analysis was to develop a pharmacokinetic model for insulin administered via the intravenous, subcutaneous, and inhalation routes. A 2-compartment pharmacokinetic model with 1 (inhaled) or 2 sequential (subcutaneous) first-order absorption processes and first-order elimination was developed using data from 2 studies with a total of 651 concentrations from 16 healthy volunteers. Insulin was administered intravenously (5 U), subcutaneously (10 U), and via inhalation (25, 50, and 100 U). The data were modeled simultaneously with NONMEM VI, using ADVAN6 subroutine with FO. Typical values were clearance, 43.4 L/h; volume of distribution in the central compartment, 5.0 L; intercompartmental clearance, 23.9 L/h; volume of distribution in the peripheral compartment 30.7 L; TI first-order absorption rate constant, 2.35 h⁻¹; and first-order absorption rate constants associated with subcutaneously administered insulin, 0.63 and 1.04 h⁻¹, respectively. Absorption rate after subcutaneous dosing was found to decrease with increasing body mass index. Insulin pharmacokinetics were found to be consistent with 2-compartment disposition, regardless of route of administration, with insulin curve differences attributable to absorption differences.