PURPOSE: To exploit the intravoxel incoherent motion (IVIM) diffusion-weighted (DW) MRI when evaluating the therapeutic response of gastrointestinal stromal tumors (GIST) to Imatinib in a mouse model. MATERIALS AND METHODS: Mice with xenografts bearing cells from the GIST-T1 cell line were randomly divided into a treated group receiving Imatinib and a control group. DWMRI scans with 14 b-values (0-1500 s/mm2) were performed before and after treatment (days 1, 3 and 7). IVIM related parameters perfusion fractions (fp) and perfusion-related diffusion coefficients (D*) and the conventional apparent diffusion coefficients (ADC) were calculated by fitting the DWMRI signal decay. The mean changes from baseline to each post-treatment time point for each measurement (DeltaADC, Deltafp and DeltaD*) were calculated. The differences of mean changes between the two groups were tested for statistical significance. Histopathological analyses including Ki-67, CD31, TUNEL and H&E were conducted in conjunction with the MRI scans. RESULTS: Increases in ADC of the treated group were higher than those of the control group after treatment, whereas statistical significances were not observed. Compared to the control group, D* in the treated group decreased significantly (DeltaD*treated = -41%, -49%, and -49% with P = 0.0001, 0.0001 and 0.0001), and fp increased significantly (Deltafptreated = 79%, 82% and 110%, with P = 0.001, 0.0001 and P = 0.0007) on days 1, 3 and 7 after treatment. Histopathological analyses demonstrated different tumor tissue characteristics between the treated and control groups. CONCLUSION: IVIM measurements may serve as more sensitive imaging biomarkers than ADC when assessing GIST response to Imatinib as early as one day after treatment.