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Purpose: To obtain the optimal simultaneous-multislice (SMS)—accelerated diffusion-weighted imaging (DWI) of the liver at 3.0 T MRI by systematically estimating the repeatability of apparent diffusion coefficient (ADC), signal-to-noise ratio (SNR) and image quality of different breathing schemes in comparison to standard DWI (STD) and other SMS sequences. Methods: In this institutional review board-approved prospective study, hepatic DWIs (b = 50, 300, 600 s/mm2) were performed in 23 volunteers on 3.0 T MRI using SMS and STD with breath-hold (BH-SMS, BH-STD), free-breathing (FB-SMS, FB-STD) and respiratory-triggered (RT-SMS, RT-STD). Reduction of scan time with SMS-acceleration was calculated. ADC and SNR were measured in nine anatomic locations and image quality was assessed on all SMS and STD sequences. An optimal SMS-DWI was decided by systematically comparing the ADC repeatability, SNR and image quality among above DWIs. Results: SMS-DWI reduced scan time significantly by comparison with corresponding STD-DWI (27 vs. 42 s for BH, 54 vs. 78 s for FB and 42 vs. 97 s for RT). In all DWIs, BH-SMS had the greatest intraobserver agreement (intraclass correlation coefficient (ICC): 0.920–0.944) and good interobserver agreement (ICC: 0.831–0.886) for ADC measurements, and had the best ADC repeatability (mean ADC absolute differences: 0.046–0.058 × 10−3mm2/s, limits of agreement (LOA): 0.010–0.013 × 10−3mm2/s) in nine locations. BH-SMS had the highest SNR in three representative sections except for RT-STD. There were no significant differences in image quality between BH-SMS and other DWI sequences (median BH-SMS: 4.75, other DWI: 4.5–5.0; P > 0.0.5). Conclusion: BH-SMS provides considerable scan time reduction with good image quality, sufficient SNR and highest ADC repeatability on 3.0 T MRI, which is thus recommended as the optimal hepatic DWI sequence for those subjects with adequate breath-holding capability. [ABSTRACT FROM AUTHOR]