Objectives To investigate the feasibility and effectiveness of SMS rs-EPI for evaluating breast lesions. Methods This prospective study was approved by IRB. Ninety-six patients had 102 histopathologically verified lesions (80 malignant and 22 benign) that were evaluated. Conventional rs-EPI and SMS rs-EPI data were acquired on a 3T scanner. Mean kurtosis (MK), mean diffusion (MD), and apparent diffusion coefficient (ADC) values were quantitatively calculated for each lesion on both sequences. Images were qualitatively and quantitatively analyzed with respect to image sharpness, geometric distortion, lesion conspicuity, anatomic structure, overall image quality, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR). Student's t test, Pearson correlation, receiver operating characteristic curve, Wilcoxon rank sum test, and paired-sample t tests were used for statistical analysis. Results Compared to conventional rs-EPI, the acquisition time of SMS rs-EPI was markedly reduced (2:17 min vs 4:27 min). Pearson's correlations showed excellent linear relationships for each parameter between conventional rs-EPI and SMS rs-EPI (MK, r = 0.908; MD, r = 0.938; and ADC, r = 0.975; p < 0.01 for all). Furthermore, SMS rs-EPI had similar diagnostic performance compared with conventional rs-EPI. SMS rs-EPI had comparable visual image quality as conventional rs-EPI, with excellent inter-reader reliability (ICC = 0.851-0.940). No differences existed between conventional rs-EPI and SMS rs-EPI for either SNR or CNR (p > 0.05). Conclusions Applying the SMS technique can significantly reduce the acquisition time and produce similar diagnostic accuracy while generating comparable image quality as the conventional rs-EPI. Key Points SMS rs-EPI reduces scan time from 4:27 min to 2:17 min compared with conventional rs-EPI. SMS rs-EPI has a comparable diagnostic performance to conventional rs-EPI in the differentiation between malignant and benign breast lesions. SMS rs-EPI demonstrates comparable image quality to conventional rs-EPI with shorter scan time.