BACKGROUND AND PURPOSE: DSC perfusion MR imaging assumes that the contrast agent remains intravascular; thus, disruptions in the blood-brain barrier common in brain tumors can lead to errors in the estimation of relative CBV. Acquisition strategies, including the choice of flip angle, TE, TR, and preload dose and incubation time, along with post hoc leakage-correction algorithms, have been proposed as means for combating these leakage effects. In the current study, we used DSC-MR imaging simulations to examine the influence of these various acquisition parameters and leakage-correction strategies on the faithful estimation of CBV. MATERIALS AND METHODS: DSC-MR imaging simulations were performed in 250 tumors with perfusion characteristics randomly generated from the distributions of real tumor population data, and comparison of leakage-corrected CBV was performed with a theoretic curve with no permeability. Optimal strategies were determined by protocol with the lowest mean error. RESULTS: The following acquisition strategies (flip angle/TE/TR and contrast dose allocation for preload and bolus) produced high CBV fidelity, as measured by the percentage difference from a hypothetic tumor with no leakage: 1) 35°/35 ms/1.5 seconds with no preload and full dose for DSC-MR imaging, 2) 35°/25 ms/1.5 seconds with 1 ⁄4 dose preload and 3 ⁄4 dose bolus, 3) 60°/35 ms/2.0 seconds with 1 ⁄2 dose preload and 1 ⁄2 dose bolus, and 4) 60°/35 ms/1.0 second with 1 dose preload and 1 dose bolus. CONCLUSIONS: Results suggest that a variety of strategies can yield similarly high fidelity in CBV estimation, namely those that balance T1-and T2*-relaxation effects due to contrast agent extravasation. ABBREVIATIONS: AIF ϭarterial input function; Bidir ϭ bidirectional leakage correction algorithm; CNR ϭ contrast-to-noise ratio; EES ϭ extravascular extracellular space; K trans ϭ efflux rate of contrast agent from the vasculature; rCBV ϭ relative CBV; Unidir ϭ unidirectional leakage correction algorithm