Background The choice between different diffusion-weighted imaging (DWI) techniques is difficult as each comes with tradeoffs for efficient clinical routine imaging and apparent diffusion coefficient (ADC) accuracy. Purpose: To quantify signal-to-noise-ratio (SNR) efficiency, ADC accuracy, artifacts, and distortions for different DWI acquisition techniques, coils, and scanners. Study Type: Phantom, in vivo intraindividual biomarker accuracy between DWI techniques and independent ratings. Population/Phantoms: NIST diffusion phantom. 51 Patients: 40 with prostate cancer and 11 with head-and-neck cancer at 1.5 T Field Strength/Sequence: Echo planar imaging (EPI): 1.5 T and 3 T Siemens; 3 T Philips. Distortion-reducing: RESOLVE (1.5 and 3 T Siemens); Turbo Spin Echo (TSE)-SPLICE (3 T Philips). Small field-of-view (FOV): ZoomitPro (1.5 T Siemens); IRIS (3 T Philips). Head-and-neck and flexible coils. Assessment: SNR Efficiency, geometrical distortions, and susceptibility artifacts were quantified for different b-values in a phantom. ADC accuracy/agreement was quantified in phantom and for 51 patients. In vivo image quality was independently rated by four experts. Statistical Tests: QIBA methodology for accuracy: trueness, repeatability, reproducibility, Bland–Altman 95% Limits-of-Agreement (LOA) for ADC. Wilcoxon Signed-Rank and student tests on P < 0.05 level. Results: The ZoomitPro small FOV sequence improved b-image efficiency by 8%–14%, reduced artifacts and observer scoring for most raters at the cost of smaller FOV compared to EPI. The TSE-SPLICE technique reduced artifacts almost completely at a 24% efficiency cost compared to EPI for b-values ≤500 sec/mm2. Phantom ADC 95% LOA trueness were within ±0.03 × 10−3 mm2/sec except for small FOV IRIS. The in vivo ADC agreement between techniques, however, resulted in 95% LOAs in the order of ±0.3 × 10−3 mm2/sec with up to 0.2 × 10−3 mm2/sec of bias. Data Conclusion ZoomitPro for Siemens and TSE SPLICE for Philips resulted in a trade-off between efficiency and artifacts. Phantom ADC quality control largely underestimated in vivo accuracy: significant ADC bias and variability was found between techniques in vivo. Level of Evidence: 3 Technical Efficacy Stage: 2