Whole-body DWI is increasingly used to assess bone involvement in prostate cancer. Multicompartmental diffusion modeling can outperform conventional DWI techniques for evaluating tumors, but has yet to be applied to whole-body imaging. In this study, we determined an optimal multicompartmental model for describing whole-body diffusion and applied it to examine metastatic bone lesions in vivo. We found that a 4-compartment model best characterized whole-body diffusion. Compartmental signal-contributions revealed by this model show improved bone-lesion conspicuity and may help to assess microstructural changes that accompany prostate-cancer bone involvement.