Adherence of proteins, cells, and microorganisms to the surface of venous catheters contributes to catheter occlusion, venous thrombosis, thrombotic embolism, and infections. These complications lengthen hospital stays and increase patient morbidity and mortality. Current technologies for inhibiting these complications are limited in duration of efficacy and may induce adverse side effects. To prevent complications over the life span of a device without using active drugs, we modified a catheter with the nonleaching polymeric sulfobetaine (polySB), which coordinates water molecules to the catheter surface. The modified surface effectively reduced protein, mammalian cell, and microbial attachment in vitro and in vivo. Relative to commercial catheters, polySB-modified catheters exposed to human blood in vitro had a >98% reduction in the attachment and a significant reduction in activation of platelets, lymphocytes, monocytes, and neutrophils. Additionally, the accumulation of thrombotic material on the catheter surface was reduced by >99% even after catheters were exposed to serum in vitro for 60 days. In vivo, in a highly thrombogenic canine model, device- and vessel-associated thrombus was reduced by 99%. In vitro adherence of a broad spectrum of microorganisms was reduced on both the external and the internal surfaces of polySB-modified catheters compared to unmodified catheters. When unmodified and polySB-modified catheters were exposed to the same bacterial challenge and implanted into animals, 50% less inflammation and fewer bacteria were associated with polySB-modified catheters. This nonleaching, polySB-modified catheter could have a major impact on reducing thrombosis and infection, thus improving patient health.