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The scope of this work was to systematically evaluate the reproducibility of diffusion-weighted imaging and the impact of b values used for apparent diffusion coefficient (ADC) calculation as well as the echo time (TE) on the resulting ADC in phantom studies. We attempted to find a minimum upper b value needed for reliable ADC measurements. In addition, we were able to investigate these impacts not only for different diffusivities but also for different T2 relaxation times. The influence of different b values on ADC calculations for different organs was also assessed in a volunteer study.Diffusion-weighted imaging of a phantom consisting of 16 compartments with combinations of 4 different diffusivities and 4 different T2 relaxation times was conducted 5 times using 11 b values (0–1000 s/mm2) and 5 different TEs. Apparent diffusion coefficient was calculated from the 16 compartment regions of interest using 42 different combinations of b values. Reproducibility of ADC was assessed from the coefficient of variation of the 5 measurements. The ADC stability was determined from a voxel-based coefficient of variation (CVsta) and the signal-to-noise ratio (SNR) to find the minimum upper b values for a reliable ADC quantification. The influence of TE on ADC quantification was assessed for 9 different b value combinations. The influence of 9 different b value combinations on ADC was evaluated by a region of interest analysis of 7 organs in 12 volunteers.The found coefficient of variation was between 10.2% and 1.4%, decreasing with increasing upper b value and increasing diffusivities. Accordingly, CVsta and SNR showed the same trend. Using an upper b value of 600 s/mm2 gives already reliable ADC results showing a maximum CVsta of 7.5%, whereas an upper b value of 1000 s/mm2 revealed a maximum CVsta of 5.5%. Values of ADC reduced with increasing upper b value in phantom as well as in human data. Apparent diffusion coefficient also reduced with increasing TE and tended to increase for increasing T2 relaxation times and increasing diffusion restriction.Apparent diffusion coefficient can be measured with high reproducibility but strongly depends on b values used and TE, which should be kept constant in each examination protocol. Whereas upper b values as low as 400 s/mm2 can be used for examinations of tissues with low diffusivities, very high b values (>1000 s/mm2) are needed to reach an optimal SNR for high diffusive tissues. An upper b value of 600 s/mm2 is a good compromise regarding ADC stability, SNR, and measurement time for all tissue types.