To evaluate the reliability and diagnostic performance of dual-energy CT virtual non-calcium imaging in diagnosing bone marrow infiltration in multiple myeloma. Seventy-two patients with multiple myeloma and ten controls were recruited. Patients received dual-energy CT and MRI while controls underwent dual-energy CT only, covering the cervical, thoracic, and lumbar spine and the pelvis. Virtual non-calcium images were compared with magnetic resonance images for confirmation and pattern classification. Fleiss Kappa analysis assessed consistency between virtual non-calcium and MRI classifications. Inter-observer agreement for virtual non-calcium and CT attenuation values was evaluated using Bland-Altman analysis. Diagnostic performances across various sites were evaluated using analysis of variance and receiver operating characteristic curve analysis. Dual-energy CT achieved higher consistency in classifying bone marrow infiltration in multiple myeloma than did MRI (kappa = 0.944). In the overall analysis, the mean virtual non-calcium attenuation values in the bone marrow infiltration group (- 28.3 HU; 95% confidence interval (CI), - 32.1, - 24.6) were higher than those in the non-bone marrow infiltration (- 97.5 HU; 95% CI, - 104.7, - 90.3) and control (- 89.1 HU; 95% CI, - 95.1, - 83.1; F = 172.027, P < 0.001) groups. The optimal cutoff values for virtual non-calcium attenuation varied across the overall (- 42.2 HU), cervical spine (- 21.9 HU), thoracic spine (- 42.8 HU), lumbar spine (- 56.9 HU), and pelvis (- 66.3 HU). Dual-energy CT virtual non-calcium imaging and MRI exhibited good consistency in categorising bone marrow infiltration patterns in multiple myeloma. Different virtual non-calcium attenuation value cutoffs should be used to diagnose bone marrow infiltration in various body regions.