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The aim of this study was to assess the robustness of an accelerated and optimized diffusion-weighted sequence in clinical routine abdominal imaging using the simultaneous multislice (SMS) technique for scan time reduction and 3-dimensional (3D) diagonal diffusion mode to optimize image quality.One hundred fifty consecutive patients received clinically indicated magnetic resonance imaging for abdominal imaging including an optimized SMS diffusion-weighted sequence (DWIOPT: diffusion mode 3D diagonal; SMS factor 2; scan time 1:44 minutes). A subgroup of 41 patients additionally received a standard diffusion-weighted sequence as reference (DWISTD: diffusion mode 4-scan trace; scan time 2:35 minutes). Qualitative and quantitative image parameters of DWISTD and DWIOPT were assessed and compared interindividually within the subgroup using dedicated statistics.In all patients, image quality ratings in DWIOPT were rated very high (overall image quality, 4.6 [4–5]; contour sharpness of right/left hepatic lobe, 4.6 [4–5]/4.4 [4–5]; and lesion conspicuity, 4.5 [4.5–5]). Interindividually, DWIOPT proved superior to DWISTD in comparison of overall image quality (4.6 [4.6–4.7] vs 4.2 [4.1–4.2]; P = 0.025) and contour sharpness of the right/left hepatic lobe (4.6 [4.5–4.7]/4.3 [4.0–4.3] vs 4.3 [4.1–43]/4.0[3.0–4.0]; each P = 0.045); lesion conspicuity was comparable in DWIOPT and DWISTD (4.0 [4.8–5] vs 4.4 [4–5]; P = 0.461), and apparent diffusion coefficient (ADC) values showed no statistically significant difference (ADCOPT vs ADCSTD: right hepatic lobe, P = 0.084; kidney, P = 0.445). Interreader agreement was substantial with a kappa value of 0.78 (P < 0.001).Diffusion-weighted imaging of the abdomen can be considerably accelerated and optimized integrating the SMS technique and a 3D diagonal diffusion mode. In a large patient cohort, this approach proved of superior image quality while maintaining similar ADC values compared with standard DWI. This technique seems applicable for daily clinical routine.