AbstractPurposeTo define an optimal set ofb‐values for accurate derivation of diffusion MRI parameters in the brain with segmented Intravoxel Incoherent Motion (IVIM) model.MethodsSimulations of diffusion signals were performed to define an optimal set ofb‐values targeting different perfusion regimes, by relying on an optimization procedure which minimizes the total relative error on estimated IVIM parameters computed with a segmented fitting procedure. Then, the optimalb‐values set was acquired in vivo on healthy subjects and skull base chordoma patients to compare the optimized protocol with a clinical one.ResultsThe total relative error on simulations decreased of about 40% when adopting the optimal set of 13b‐values (0 10 20 40 50 60 200 300 400 1200 1300 1400 1500 s/mm2), showing significant differences and increased precision on D and f estimates with respect to simulations with a non‐optimizedb‐values set. Similarly, in vivo acquisitions demonstrated a dependency of IVIM parameters on theb‐values array, with differences between the optimal set ofb‐values and a clinical non‐optimized acquisition. IVIM parameters were compatible to literature values, withD(0.679/0.701 [0.022/0.008] ·10−3mm2/s),f(5.49/5.80 [0.70/1.14] %), andD* (8.25/7.67 [0.92/0.83] ·10−3mm2/s) median [interquartile range] estimates for white matter/gray matter in volunteers andD(0.709/0.715/1.06 [0.035/0.023/0.271] ·10−3mm2/s),f(7.08/7.84/21.54 [1.20/1.06/6.05] %), andD* (10.85/11.84/2.32 [1.38/2.32/4.94] ·10−3mm2/s) for white matter/gray matter/Gross Tumor Volume in patients with skull‐base chordoma tumor.ConclusionsThe definition of an optimalb‐values set can improve the estimation of quantitative IVIM parameters. This allows setting up an optimized approach that can be adopted for IVIM studies in the brain.