Purpose: To report a study evaluating the safety and efficacy of stenting via direct carotid access with flow reversal using the ENROUTE Transcarotid Neuroprotection System. Methods: Between March 2009 and June 2012, 75 patients (mean age 72.6 years; 45 men) underwent carotid artery stenting with the ENROUTE System; the majority of patients (63, 84%) were asymptomatic. The primary safety endpoint was the composite of major stroke, myocardial infarction, or death at 30 days. Efficacy outcomes included acute device success, procedure success, and tolerance to flow reversal. Fifty-six (74.7%) patients underwent diffusion-weighted magnetic resonance imaging (DW-MRI) before and after the procedure to assess the development of new ischemic brain lesions. Results: Acute device and procedure success were achieved in 68 (90.6%) patients. The reverse flow circuit was established in 71 (94.6%) patients; only 5 patients demonstrated transient intolerance to flow reversal that did not interfere with completion of the procedure. The mean time on flow reversal was 19.1 minutes. In the DW-MRI substudy, 10 (17.9%) of 56 patients had ipsilateral new white lesions with a mean volume of 0.17 mL. At 30 days, no major stroke, myocardial infarction, or death occurred; 1 patient had experienced a minor stroke that was adjudicated as not related to either the device or procedure. Conclusion: Results of the PROOF study demonstrate the safety and efficacy of transcarotid revascularization with the ENROUTE Transcarotid Neuroprotection System.