Purpose: Percutaneous lower extremity revascularization is being performed via upper extremity, pedal, or popliteal access with increasing frequency. This study aimed to compare periprocedural outcomes of popliteal (POA) and upper extremity (UEA) access for the treatment of isolated superficial femoral artery (SFA) occlusive disease. Materials and Methods: A retrospective cohort study compared the outcomes of patients undergoing primary percutaneous intervention of SFA occlusive disease with POA or UEA using the Vascular Quality Initiative database from December 2010 to June 2019. Our primary endpoint was technical success. Secondary endpoints included factors associated with perioperative complications. Results: A total of 349 patients underwent isolated SFA intervention through the popliteal, radial, or brachial artery. UEA was performed in 188 (53.9%) patients and POA in 161 (46.1%). Technical success with TASC A lesions was 95.8% and with TASC D lesions, 65.0%. POA had a higher proportion of TASC D lesions (24.8% vs 10.6%, p<0.001), and larger (≥7 Fr) sheath size (14.3% vs 2.7%, p<0.001). UEA had a higher proportion of no calcification (27.1% vs 11.2%, p<0.001), and smaller (4–5 Fr) sheath size (46.8% vs 34.8%, p=0.023). There was no difference in technical success between UEA and POA (88.8% vs 84.5%, p=0.230), which was also seen on multivariable analysis (p=0.985). Univariate analysis revealed technical failure was associated with TASC D lesions (45.7% vs 12.9%, p<0.001) and the presence of severe calcifications (39.1% vs 17.5%, p=0.002). Multivariable analysis confirmed technical failure was associated with degree of calcification (OR, 2.4; 95% CI, 1.18 to 4.89; p=0.016) and TASC D lesions (OR, 5.01; 95% CI, 2.45 to 10.24; p<0.001). Postoperative complications were associated with UEA on univariate (p=0.041) and multivariate analysis (OR, 2.08; 95% CI, 0.80 to 5.37; p=0.016). Access site complications were also associated with UEA compared to POA (4.3% vs 0.0%, p=0.027). Conclusions: There is no difference in technical success between UEA and POA when treating isolated SFA occlusive disease, and UEA is associated with a higher complication rate. Technical success is dependent on calcification and TASC II classification. Based on similar technical success rates and low complication rates, POA should be considered as a viable alternative to UEA when planning endovascular interventions.