E-selectin, an early mediator of leukocyte-endothelial adhesion, is expressed on activated endothelium. Soluble E-selectin is present in the supernatant of cytokine-activated endothelial cells and elevated serum levels are found in a variety of inflammatory conditions. We documented elevated E-selectin serum levels in 119 critically ill medical ICU patients (log transformed mean E-selectin level, measured by ELISA, was 5.28 ng/ml) compared to normal volunteers (1 ng/ml). Forty-three patients with culture-positive sepsis had higher (p < 0.05) E-selectin levels (15.39 ng/ml) than 24 patients with culture-negative sepsis (4.87 ng/ml), 44 with noninfectious SIRS (2.33 ng/ml), and eight without SIRS (1.97 ng/ml). E-selectin levels related strongly to the degree of hemodynamic compromise (p < 0.0001). Further analysis demonstrated microbiological status and hemodynamic status to be independent variables related to E-selectin level. Day 1 E-selectin levels correlated positively with peak organ failure score over the course of ICU hospitalization (r = 0.30, p = 0.001) and were higher (p < 0.05) for nonsurvivor (10.61 ng/ml, n = 26) than survivors (4.35 ng/ml, n = 93). We conclude that soluble E-selectin levels are higher in serum of patients with microbiologically documented sepsis than in other critically ill medical ICU patients. Day 1 E-selectin levels correlate highly with hemodynamic compromise and modestly with subsequent organ dysfunction and survival.