Restriction spectrum imaging (RSI) is an advanced quantitative diffusion-weighted magnetic resonance imaging (DWI) technique to assess breast cancer. To investigate the ability of RSI to differentiate the benign and malignant breast lesions and the association with prognostic factors of breast cancer. Retrospective. Seventy women (mean age, 49.6 ± 12.3 years) with 56 malignant and 19 benign breast lesions. 3-T; RSI-based DWI sequence with echo-planar imaging technique. The apparent diffusion coefficient (ADC) and RSI parameters (restricted diffusion f1 , hindered diffusion f2 , free diffusion f3 , and signal fractions f1 f2 ) were calculated by two readers for the whole lesion volume and compared between the benign and malignant groups and the subgroups with different statuses of prognostic factors in breast cancer. Mann-Whitney U test or Student's t-test was applied to compare the quantitative parameters between the different groups. Intraclass correlation coefficient (ICC) was used to assess readers' reproducibility. Binary logistic regression was used to combine parameters. Area under the curve (AUC) of receiver operating characteristic curve analysis was used to evaluate the diagnostic performance of parameters to distinguish benign from malignant breast lesions. A P-value <0.05 was considered statistically significant. Malignant breast lesions showed significantly lower ADC and f3 values, and significantly higher f1 and f1 f2 values than the benign lesions, with AUC of 0.951, 0.877, 0.868, and 0.860, respectively. When RSI-derived parameters and ADC were combined, the diagnostic performance was superior to either single parameter (AUC=0.973). The f3 value was significantly differed between estrogen receptor (ER)-positive and ER-negative tumors. The ADC, f1 , f3 , and f1 f2 values were significantly different progesterone receptor (PR)-positive and PR-negative status. The RSI-derived parameters (f1 , f3 , and f1 f2 ) may facilitate the differential diagnosis between benign and malignant breast lesions. 4 TECHNICAL EFFICACY: Stage 2.