AbstractAlthough there have been many advancements in cancer research, much is still unknown about the heterogeneous tumor microenvironment. Diffusion‐weighted MRI has proven to be a viable and versatile microstructural probe. Diffusion‐weighted sequences specifically sensitive to intravoxel incoherent motion (IVIM) have seen a recent resurgence of interest as they promise to provide a valuable window on the vascular microenvironment. To understand, test, and optimize IVIM‐sensitive approaches, a complex flow phantom was constructed to mimic certain characteristics of the tumor microenvironment such as tortuous microvasculature, heterogeneous vascular permeability, and interstitial fluid pressure buildup. Results using this phantom on a clinical scanner platform confirmed IVIM sensitivity to microscopic flow effects. Biexponential fitting of signal decay curves enabled quantitative extraction of perfusion fraction, IVIM‐related pseudodiffusivity, and tissue diffusivity. Parametric maps were also generated, illustrating the potential utility of IVIM‐sensitive imaging in clinical settings. The flow phantom proved to be an effective test‐bed for validating and optimizing the IVIM‐MRI technique to provide surrogate markers for microvascular properties. Magn Reson Med, 2011. © 2011 Wiley Periodicals, Inc.