To investigate the diagnostic value of tumor homogeneity on contrast-enhanced (CE) computed tomography (CT) to differentiate multiple myeloma (MM) from osteolytic bone metastases (Mets). This retrospective study included patients who were diagnosed with MM or Mets and had multiple (≥2) osteolytic bone tumors on pre-treatment CE-CT. Intratumoral homogeneity was assessed by coefficient of variation (CV, ratio of standard deviation to mean) of the density of a single lesion (CV-lesion). Intertumoral homogeneity was assessed as the CV of the densities of multiple lesions in one patient (CV-patient). A classification model was built from CT parameters using classification and regression tree (CART) analysis. Diagnostic performance of the model was evaluated using C-statistics. A total of 272 lesions (81 MM and 191 Mets) of 105 patients were analyzed. The mean CV-lesion and CV-patient of MM were significantly lower than those of Mets: 0.17 vs 0.26 for CV-lesion (p = 0.005) and 0.16 vs 0.23 for CV-patient (p = 0.013). Thickened struts were more common in MM than in Mets (49.1% vs 12.8%, p ≤ 0.001). In CART analysis, CV-lesion was the first partitioning predictor, followed by thickened struts and by CV patient. The CART model could distinguish MM from Mets in both the model development cohort (C-statistic: 0.843) and the temporal validation cohort (0.721, 0.686, and 0.686 for three reviewers, respectively). MM showed intratumoral and intertumoral homogeneity compared with Mets on CE-CT. The combination of CV-lesion and CV-patient can be helpful to radiologists in differentiation of MM from Mets. Our study showed that MM had intratumoral and intertumoral homogeneity compared with Mets on contrast-enhanced CT.