Background: Evaluating the severity of peripheral artery lesions is challenging. Image-based blood flow modeling from peripheral Computed Tomographic Angiography (pCTA) may provide a non-invasive method to determine the hemodynamic significance of lesions. This pilot study evaluates the performance of pCTA-based blood flow modeling in diagnosing functionally significant peripheral lesions in comparison with Digital Subtraction Angiography (DSA). Methods: Ten patients undergoing DSA and pCTA were included. The peripheral arteries were divided into 8 segments per extremity and stenosis severity was graded by visual estimation from DSA. Each segment was graded 0 to IV (normal, mildly-stenotic, moderately-stenotic, severely-stenotic, occluded) or non-evaluable. Independent from DSA review, a Resting Pressure Drop (RPD) and an Exercise Pressure Drop (ExPD) for each segment was calculated from pCTA-based blood flow modeling. A functionally significant (FS) lesion was defined as grade III or IV by DSA and RPD > 5 mmHg from pCTA-based modeling. Analysis was repeated with an ExPD > 20 mmHg. Sensitivity, specificity and accuracy were calculated for RPD > 5 mmHg and ExPD > 20 mmHg using DSA as the standard. Results: Mean age was 52±16 years, 4 patients were male, 8 patients presented with critical limb ischemia, mean ankle brachial index was 0.60±0.29, and 66 arterial segments were available for both assessment methods. Twenty-two segments had FS lesions by DSA. Using an RPD > 5 mmHg, sensitivity was 80%, specificity was 85% and accuracy was 79%. Using an ExPD > 20 mmHg, sensitivity was 84%, specificity was 89% and accuracy was 88%. Conclusion: Use of a resting pressure drop > 5 mmHg and an exercise pressure drop > 20 mmHg, measured by blood flow modeling from CT angiography, can accurately identify functionally significant stenosis in patients with peripheral vascular disease. This information motivates the need for a larger-scale prospective imaging trial to further validate this novel non-invasive approach.