Introduction <p>Rituximab, an anti-cluster of differentiation (CD)-20 monoclonal antibody, is used in the treatment of non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia, and rheumatoid arthritis. The pharmacokinetics of rituximab have been reported to be target mediated, but this alone may not fully explain the nonlinear decay of its concentrations over time. </p> Objective <p>This study aimed to explore the potential role of immunoglobulin (Fc gamma receptor; FcγR) and neonatal Fc receptor (FcRn) in the disposition of rituximab. </p> Methods <p>Concentration–time data from 108 patients with NHL, 118 with chronic lymphocytic leukemia, and 90 with rheumatoid arthritis were collected to refine a two-compartment population pharmacokinetic model with target-mediated drug disposition and irreversible binding approximation. Non-specific rituximab elimination was described using an intercompartment FcRn-mediated disposition model. Additionally, rituximab was assumed to bind to FcγR-expressing cells in both central and peripheral compartments; its disposition resulting from these mechanisms was described using quasi-steady-state interaction models.</p> Results <p>The FcRn-mediated disposition model provided a satisfactory description of the data and was further improved by incorporating central and peripheral FcγR quasi-steady-state interaction models with steady-state dissociation constants estimated at 586 and 418 nM, respectively. CD19 cell count was related to target-mediated elimination rate constant (<i>p</i> = 1.7 × 10^-8) and inversely related to non-specific elimination (assessed by estimated FcRn amount, <i>p</i> = 2.1 × 10^-8). In patients with NHL, FcγR levels in central and peripheral compartments increased with baseline metabolic tumor volume (<i>p</i> = 7.0 × 10^-6 and <i>p</i> = 5.0 × 10^-28, respectively). </p> Conclusion <p>The pharmacokinetics of rituximab are mediated both by Fab (target) interactions and by FcγR and FcRn interactions.</p> Graphical Abstract <p></p>