Background and purposeQuantitative Diffusion Weighted Imaging (DWI) has great potential in guiding head and neck (HN) cancer radiotherapy. However, clinical translation has been hindered by severe distortions in standard single-shot Echo-Planar-Imaging (ssEPI) and prolonged scan time and low SNR in Turbo-Spin-Echo (ssTSE) sequences. In this study, we evaluate “multi-shot” (ms) msEPI and msTSE acquisitions in the context of HN radiotherapy. Materials and methodsssEPI, ssTSE, msEPI with 2 and 3 shots (2sEPI, 3sEPI), and msTSE DWI were acquired in a phantom, healthy volunteers (N=10), and patients with HN cancer (N=5) on a 3-Tesla wide-bore MRI in radiotherapy simulation RF coil setup, with matched spatial resolution (2x2x5mm) and b = 0,200,800 s/mm2.Geometric distortions measured with deformable vector field (DVF) and contour analysis, apparent diffusion coefficient (ADC) values, and signal-to-noise-ratio efficiency (SNReff) were quantified for all scans. ResultsAll techniques significantly (P<1x10-3) reduced distortions compared with ssEPI (DVFmean = 3.1 ± 1.3 mm). Distortions were marginally lower for msTSE (DVFmean = 1.5 ± 0.6 mm) than ssTSE (1.8 ± 0.9 mm), but were slightly higher with 2sEPI and 3sEPI (2.6 ± 1.0 mm, 2.2 ± 1.0 mm). SNReff reduced with decreasing distortion with ssEPI=21.9 ± 7.9, 2sEPI=15.1 ± 5.0, 3sEPI=12.1 ± 4.5, ssTSE=6.0 ± 1.6, and msTSE=5.7 ± 1.9 for b = 0 images. Phantom ADC values were consistent across all protocols (errors ≤ 0.03x10-3mm2/s), but in vivo ADC values were ∼ 4 % lower with msEPI and ∼ 12 % lower with ssTSE/msTSE compared with ssEPI. ConclusionsmsEPI and TSE acquisitions exhibited improved geometric distortion at the cost of SNReff or scan time. While msTSE exhibited the least distortion, 3sEPI may offer an appealing middle-ground with improved geometric fidelity but superior efficiency and in vivo ADC quantification.