Purpose To evaluate the apparent diffusion coefficients (ADCs) of magnetic resonance (MR) imaging patterns in the bone marrow of patients with multiple myeloma (MM) and to determine a threshold ADC that may help distinguish a diffuse from a normal pattern with high accuracy. Materials and Methods This prospective study was approved by the ethics review board, and informed consent was obtained. Ninety-nine patients with newly diagnosed, untreated MM and 16 healthy control subjects underwent spinal MR imaging including diffusion-weighted imaging, and bone marrow ADCs were calculated. Pattern assignment was based on visual assessment of conventional MR images. The Kruskal-Wallis H test, the Mann-Whitney test, and the one-way analysis of variance were used to compare ADCs between patient subsets and control subjects, and a receiver operating characteristic analysis was performed. Results Mean ADCs ± standard deviation in patients with MM for the normal, focal, and diffuse MR imaging patterns were 0.360 × 10-3 mm2/sec ± 0.110, 1.046 × 10-3 mm2/sec ± 0.232, and 0.770 × 10-3 mm2/sec ± 0.135, respectively. There were significant differences in ADCs between diffuse and normal (P < .001), diffuse and focal (P < .001), and focal and normal (P < .001) patterns. Patients with a diffuse pattern had more features of advanced disease, higher international staging system score, increased incidence of high-risk cytogenetics, and higher revised international staging system score. ADCs greater than 0.548 × 10-3 mm2/sec showed 100% sensitivity (26 of 26) and 98% specificity (48 of 49) for the diagnosis of a diffuse (vs normal) MR imaging pattern, whereas an ADC greater than 0.597 × 10-3 mm2/sec showed 96% sensitivity (25 of 26) and 100% specificity (49 of 49). Conclusion ADCs of MR imaging patterns in patients with MM differ significantly. A diffuse MR imaging pattern can be distinguished more objectively from a normal MR imaging pattern by adding quantitative diffusion-weighted imaging to standard MR imaging protocols. © RSNA, 2016 Online supplemental material is available for this article.