Synthetic materials with an innate ability to avoid the foreign-body-response remain an unrealized goal that would transform the medical device industry. The balance of bulk material properties, that enable a device to perform as intended, with surface properties, that provide bio- and hemocompatibility, has always required the former to be prioritized. While all materials used in modern devices have an acceptable level of biocompatibility, imperfection remains, ultimately leading to device failure, or requiring pharmacological intervention for it to be tolerated. Where such devices cause damage or place strain on the normal architecture of the surrounding tissue, these impacts may initiate inflammatory responses that can also led to failure. This is most evident in the treatment of vessels in the lower extremity in patients with peripheral arterial disease (PAD), where in-stent restenosis (ISR) remains a significant challenge for vascular surgeons. Blood-contacting devices, such as stents and artificial grafts, are considered particularly difficult to shield from the foreign-body-response due to the immediate and direct exposure to blood and therefore, the full gamut of the body’s immune responses. Pharmacological treatment is currently paramount to successful percutaneous vascular intervention (PVI) with antiplatelet therapies being prescribed to manage the risk of thrombosis and cytotoxic drug-eluting coatings to reduce restenosis. Here, we present data that indicate a nano-thin coating of hyperbranched polyglycerol (HPG) can greatly improve the safety and durability of endovascular metal stents. The HPG coating successfully prevents the binding and activation of platelets and greatly reduces the thrombogenicity of nitinol stents when studied ex vivo, using fresh human blood. In vivo, HPG-coated stainless-steel stents remained patent after 28 days in apolipoprotein E (ApoE) knockout mice while control stents all became completely occluded, highlighting the HPG coating’s ability to reduce restenosis. Together, these properties could help alleviate the industry’s dependence on blood-thinning and antiproliferative drugs to resolve device compatibility issues; thereby greatly improve patients’ quality of life through faster recovery, fewer complications and fewer repeat interventions. Furthermore, this coating technology is compatible with a range of materials commonly used in the production of implantable medical devices, such as stainless steel, nitinol, silicone, and polytetrafluoroethylene, while being highly scalable, cost effective and stable. Taken together, HPG presents itself as an alternative coating suitable for a broad range of vascular devices including stents and grafts.