BACKGROUND: Polymer-free amphilimus-eluting stents (PF-AES) represent a novel elution technology in the current era of drug-eluting stents. The clinical safety and efficacy of PF-AES as compared with latest-generation permanent-polymer zotarolimus-eluting stents (PP-ZES) have not yet been investigated in a large randomized trial. METHODS: In this physician-initiated, prospective, multicenter, randomized, noninferiority trial, an all-comers population requiring percutaneous coronary intervention was enrolled across 3 European sites. Randomization (1:1 ratio) to PP-ZES or PF-AES was performed after stratification for troponin status and diabetes mellitus. In both treatment arms, troponin-positive patients were planned for 12-month dual antiplatelet therapy, whereas troponin-negative patients were planned for 1-month dual antiplatelet therapy. Outcome assessors were blinded to the allocated treatment. The device-oriented primary end point of target-lesion failure was defined as cardiac death, target-vessel myocardial infarction, or target-lesion revascularization at 12-months as analyzed by modified intention-to-treat (80% power, and a 3.5% noninferiority margin). RESULTS: In total, 1502 patients were randomized and 1491 treated with the assigned stent and available for follow-up. The primary end point occurred in 42 (5.6%) of the 744 patients receiving PP-ZES versus 46 (6.2%) of the 747 patients receiving PF-AES. PF-AES were clinically noninferior to PP-ZES (risk difference, 0.5%; upper limit 1-sided 95% confidence interval, 2.6%; Pnoninferiority=0.0086). Cardiac death occurred in 10 (1.3%) versus 10 patients (1.3%; P value for difference, 1.00), target-vessel myocardial infarction occurred in 18 (2.4%) versus 17 patients (2.3%; P value for difference, 0.87), and target-lesion revascularization occurred in 22 (2.9%) versus 20 patients (2.6%; P value for difference, 0.75) for PF-AES as compared with PP-ZES. Overall, definite or probable stent thrombosis occurred in 1.0%. CONCLUSIONS: PF-AES were noninferior to PP-ZES regarding target-lesion failure at 12 months. Findings regarding the secondary end point and prespecified subgroups were generally consistent with that of the primary end point. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02328898.