Purpose: To evaluate the safety and efficacy of a novel optical coherence tomography (OCT)–guided atherectomy catheter in treating patients with symptomatic femoropopliteal disease. Methods: The VISION trial (ClinicalTrials.gov identifier NCT01937351) was a single-arm, multicenter, global investigational device exemption study enrolling 158 subjects (mean age 67.2±10.5 years; 87 men) across 20 participating sites. In this cohort, 198 lesions were treated with an average length of 53±40 mm using the Pantheris catheter alone or Pantheris + adjunctive therapy. The primary safety endpoint was the composite of major adverse events (MAEs) through 6 months (objective performance goal 43.2%). Technical success (primary efficacy outcome) was defined as the percent of target lesions with a residual diameter stenosis ≤50% after treatment with the Pantheris device alone (objective performance goal 87.0%). Procedural success was defined as reduction in stenosis to ≤30% after Pantheris ± adjunctive therapy. Tissue specimens retrieved from each treated lesion were histologically analyzed to evaluate the accuracy and precision of OCT image guidance. Results: The primary efficacy outcome was achieved in 192 (97.0%) of the 198 lesions treated with the Pantheris catheter. Across all lesions, mean diameter stenosis was reduced from 78.7%±15.1% at baseline to 30.3%±11.8% after Pantheris alone (p<0.001) and to 22.4%±9.9% after Pantheris ± adjunctive therapy (p<0.001). Of the 198 target lesions, 104 (52.5%) were treated with the Pantheris alone, 84 (42.4%) were treated with Pantheris + adjunctive angioplasty, and 10 (5.1%) with Pantheris + angioplasty + stenting. The composite MAE outcome through 6 months occurred in 25 (16.6%) of 151 subjects. There were no clinically significant perforations, 1 (0.5%) catheter-related dissection, 4 (2%) embolic events, and a 6.4% clinically driven target lesion revascularization rate at 6 months. The 40-lesion chronic total occlusion (CTO) subset (mean lesion length 82±38 mm) achieved a similar significant reduction in stenosis to 35.5%±13.6% after Pantheris alone (p<0.001). Histological analysis of atherectomy specimens confirmed <1% adventitia in 82.1% of the samples, highlighting the precision of OCT guidance. Characterization of the OCT-guided lesions revealed evidence of an underestimation of disease burden when using fluoroscopy. Conclusion: OCT-guided atherectomy for femoropopliteal disease is safe and effective. Additionally, the precision afforded by OCT guidance leads to greater removal of plaque during atherectomy while sparing the adventitia.