Multishot multiplexed sensitivity-encoding diffusion-weighted imaging is a feasible and easily implementable routine breast MRI protocol that yields high-quality diffusion-weighted breast images.Purpose: To compare multiplexed sensitivity-encoding (MUSE) diffusion-weighted imaging (DWI) and single-shot DWI for lesion visibility and differentiation of malignant and benign lesions within the breast.Materials and Methods: In this prospective institutional review board-approved study, both MUSE DWI and single-shot DWI sequences were first optimized in breast phantoms and then performed in a group of patients. Thirty women (mean age, 51.1 years ± 10.1 [standard deviation]; age range, 27-70 years) with 37 lesions were included in this study and underwent scanning using both techniques. Visual qualitative analysis of diffusion-weighted images was accomplished by two independent readers; images were assessed for lesion visibility, adequate fat suppression, and the presence of artifacts. Quantitative analysis was performed by calculating apparent diffusion coefficient (ADC) values and image quality parameters (signal-to-noise ratio [SNR] for lesions and fibroglandular tissue; contrast-to-noise ratio) by manually drawing regions of interest within the phantoms and breast tumor tissue. Interreader variability was determined using the Cohen κ coefficient, and quantitative differences between MUSE DWI and single-shot DWI were assessed using the Mann-Whitney U test; significance was defined at P < .05.Results: MUSE DWI yielded significantly improved image quality compared with single-shot DWI in phantoms (SNR, P = .001) and participants (lesion SNR, P = .009; fibroglandular tissue SNR, P = .05; contrast-to-noise ratio, P = .008). MUSE DWI ADC values showed a significant difference between malignant and benign lesions (P < .001). No significant differences were found between MUSE DWI and single-shot DWI in the mean, maximum, and minimum ADC values (P = .96, P = .28, and P = .49, respectively). Visual qualitative analysis resulted in better lesion visibility for MUSE DWI over single-shot DWI (κ = 0.70).Conclusion: MUSE DWI is a promising high-spatial-resolution technique that may enhance breast MRI protocols without the need for contrast material administration in breast screening.Keywords: Breast, MR-Diffusion Weighted Imaging, OncologySupplemental material is available for this article.© RSNA, 2020.