This investigation evaluated the utility of a physiologically based pharmacokinetic (PBPK) model, which incorporates model parameters representing key determinants of monoclonal antibody (mAb) target-mediated disposition, to predict, a priori, mAb disposition in plasma and in tissues, including tumors that express target antigens. Monte Carlo simulation techniques were employed to predict the disposition of two mAbs, 8C2 (as a non-binding control mouse IgG1 mAb) and T84.66 (a high-affinity murine IgG1 anti-carcinoembryonic antigen mAb), in mice bearing no tumors, or bearing colorectal HT29 or LS174T xenografts. Model parameters were obtained or derived from the literature. (125)I-T84.66 and (125)I-8C2 were administered to groups of SCID mice, and plasma and tissue concentrations were determined via gamma counting. The PBPK model well-predicted the experimental data. Comparisons of the population predicted versus observed areas under the plasma concentration versus time curve (AUC) for T84.66 were 95.4 ± 67.8 versus 84.0 ± 3.0, 1,859 ± 682 versus 2,370 ± 154, and 5,930 ± 1,375 versus 5,960 ± 317 (nM × day) at 1, 10, and 25 mg/kg in LS174T xenograft-bearing SCID mice; and 215 ± 72 versus 233 ± 30, 3,070 ± 346 versus 3,120 ± 180, and 7,884 ± 714 versus 7,440 ± 626 in HT29 xenograft-bearing mice. Model predicted versus observed 8C2 plasma AUCs were 312.4 ± 30 versus 182 ± 7.6 and 7,619 ± 738 versus 7,840 ± 24.3 (nM × day) at 1 and 25 mg/kg. High correlations were observed between the predicted median plasma concentrations and observed median plasma concentrations (r (2) = 0.927, for all combinations of treatment, dose, and tumor model), highlighting the utility of the PBPK model for the a priori prediction of in vivo data.