Newer-generation drug-eluting stents (DES) with enhanced biocompatibility that deliver antiproliferative drugs from a durable polymer have significantly improved safety and efficacy outcomes, compared with both early-generation DES and bare-metal stents, and they represent the current standard of care in all patient and lesion subsets. However, newer durable polymers have been associated with the occurrence of chronic inflammation, delayed vascular healing, incomplete endothelialisation, and neoatherosclerosis, which may result in persistent late adverse cardiovascular events, particularly in patients with high-risk baseline clinical features and angiographic complex coronary artery disease. Newer-generation DES with biodegradable polymer and controlled drug release have been recently introduced to overcome long-term adverse outcomes observed with both early-generation and newer-generation permanent polymer-based DES, and they may be of incremental clinical value in subgroups of patients at higher risk of stent failure. The recent ultrathin-strut cobalt-chromium Orsiro Hybrid DES (BIOTRONIK AG, Bülach, Switzerland) eluting sirolimus from a biodegradable polymer was designed to improve arterial healing and clinical outcomes. The Orsiro Hybrid DES has demonstrated clinical performance comparable to the current state-of-the-art newer-generation thin-strut cobalt-chromium, permanent polymer-based everolimus-eluting stent in a broad patient population. In subgroups of patients at highest-risk of adverse ischemic events, such as patients with diabetes mellitus, small vessels, long lesions, complex coronary lesions, multivessel disease, chronic total occlusion, or ST-segment elevation myocardial infarction, the Orsiro Hybrid DES has shown low rates of adverse clinical outcomes, similar to rates observed in lower-risk patients, and extremely low rates of definite stent thrombosis. This article reviews current evidence on safety and efficacy of the recent ultrathin-strut biodegradable polymer Orsiro Hybrid DES in high-risk subgroups.