Purpose: To compare multiplexed sensitivity encoding (MUSE) and conventional diffusion-weighted magnetic resonance imaging (cDWI) techniques in liver MRI. Methods: Fifty-nine patients who underwent both two-shot echo-planar DWI using MUSE and single-shot echoplanar cDWI at a 3.0-T MRI system were included. Qualitative parameters were independently evaluated by three radiologists, and quantitative parameters were calculated on the basis of region of interest measurements. Receiver operating characteristic curve analysis and McNemar's test were used to compare solid lesion characterization results and lesion detectability, respectively. Results: All reviewers found less image noise, sharper liver contours, milder susceptibility artifacts, and better lesion conspicuity in MUSE-DWI than in cDWI (reader average mean, 4.1-4.5 vs. 3.5-4.0; p < 0.05). The signalto-noise ratio (SNR) of the liver was significantly higher in MUSE-DWI than in cDWI (right lobe: mean, 9.39 vs. 8.10, p < 0.001; left lobe: mean, 8.34 vs. 7.19, p < 0.001), while the SNR of the lesion (mean, 23.72 vs. 23.88, p = 0.911) and lesion-to-liver contrast-to-noise ratio (mean, 14.65 vs. 15.41, p = 0.527) were comparable between MUSE-DWI and cDWI. Solid lesion characterization results were comparably accurate between MUSE-DWI and cDWI (reader average area under the receiver operating characteristic curve, 0.985 vs. 0.986, p = 0.480). The detectability of lesions was better in MUSE-DWI than in cDWI (reader consensus, 83.7 % [41/49] vs. 67.3 % [33/49], p = 0.021). Conclusion: MUSE-DWI can provide multi-shot liver DWI with less noise, fewer distortions, improved SNR of the liver, and better lesion detectability.