Poloxamer 188 (P188) is a nonionic block copolymer surfactant that has rheologic, anti-thrombotic, anti-inflammatory, and cytoprotective activities. Several mechanisms have previously been proposed, but none explain all of the observed effects. In this study, superior mesenteric artery occlusion (SMAO) was employed as a clinically relevant model of ischemia/reperfusion. The superior mesenteric artery of rats was clamped for one hr and and followed by reperfusion with P188 or saline for five hr, after which tissues were harvested for expression microarray, histologic, enzymatic, and western blot analyses. The results demonstrated that P188 significantly inhibits the entire spectrum of inflammatory, coagulation, and apoptotic responses produced by SMAO. This supports the existence of a novel mechanism that recognizes two types of adhesive interactions. The first, specific receptor-ligand adhesion, governs interactions between cells and molecules and is unaffected by P188. P188 affects only the second type, hydrophobic adhesion, which is responsible for the integrity of membranes and conformation of proteins. Hydrophobic interactions are non-specific because they derive from repulsion of water rather than from affinity of molecules for one another. Ischemic membranes develop defects that expose underlying hydrophobic structures and trigger multiple deleterious responses. Fat emboli and hydrophobic proteins such as fibrin produced by the injury further compromise the microcirculation. The unique structure of P188 facilitates its rapid, but gentle, binding to any exposed hydrophobic domain, restoring normal non-adhesive surfaces and thereby preventing activation of the entire spectrum of deleterious reactions.