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The study aimed to investigate magnetic resonance diffusion-weighted imaging (DWI) in the differentiation of uterine leiomyosarcoma (ULMS) from degenerated leiomyoma (DLM).Sixteen patients with ULMSs and 26 patients with DLMs confirmed by surgery and pathology underwent conventional magnetic resonance imaging and DWI. The mean apparent diffusion coefficient (ADC) values of the 2 groups’ tumors were measured and compared using an independent-sample t test (b = 0.1000 s/mm2 [ADC1]; b = 0.800 s/mm2 [ADC2], respectively). A receiver operating characteristic curve was used to evaluate the diagnostic performance of DWI in the differentiation of ULMS from DLM. Intraobserver and interobserver agreements were evaluated using an intraclass correlation coefficient and Bland-Altman analysis.The mean ADC value in ULMSs (0.81 ± 0.14 × 10−3mm2/s [ADC1], 0.90 ± 0.11 × 10−3mm2/s [ADC2]) was significantly lower than that in DLMs (1.22 ± 0.22 × 10−3mm2/s [ADC1], 1.50 ± 0.22 × 10−3mm2/s [ADC2]) (P < 0.001, <0.001, respectively). The sensitivity, specificity, accuracy, and positive and negative predictive values for characterizing ULMS were 100%, 90%, 93%, and 83% and 100% [ADC1] and 100%, 93%, 96%, and 90% and 100% [ADC2]; respectively. Intraobserver and interobserver reproducibilities were excellent (intraclass correlation coefficient = 0.967–0.988; small variability and 95% limits of agreement).Diffusion-weighted imaging is helpful in differentiating ULMS from DLM.