The inflammatory response in patients with necrotizing soft-tissue infection (NSTI) is excessive and often causes collateral damage, thereby worsening disease severity and prognosis. Shedding of endothelial adhesion molecules may be a key regulatory mechanism to modulate the inflammatory response in patients with septic NSTI. Hyperbaric oxygen (HBO2) treatment has demonstrated an effect on adhesion molecules. However, endothelial shedding and its association with NSTI disease severity and prognosis is not fully understood. We hypothesized that shedding of intercellular adhesion molecule-1, and the resulting release of the soluble isoform soluble intercellular adhesion molecule-1 (sICAM-1), is modified by HBO2 treatment, and that sICAM-1 concentrations are associated with severity of disease and mortality in patients with NSTI. We measured sICAM-1 in 80 patients with NSTI immediately before and after first session of HBO2 treatment as well as on the following day. We found an overall sICAM-1 level of 594 ng/mL [interquartile range (IQR) 406-817]. HBO2 significantly (P = 0.01) increased sICAM-1 by a median of 45.1 ng/mL, which remained elevated until the following day; this effect was more pronounced in patients with septic shock. Furthermore, sICAM-1 was significantly correlated with disease severity [simplified acute physiology score II (SAPS II); ρ = 0.24, P = 0.04] and low sICAM-1 was found to be an independent predictor for 90-day mortality in age-sex-SAPS II-adjusted analysis (odds ratio 14.0, 95% CI 1.82-341.4, P = 0.03). These results support the hypothesis that endothelial shedding is an important pathophysiological mechanism in NSTI and suggest that HBO2 treatment may induce immunomodulatory effects that potentially decreases collateral damage and mortality.NEW & NOTEWORTHY HBO2 treatment may be a promising immunomodulatory agent by increasing sICAM-1, thereby lowering risk of collateral damage, especially in the most critically ill patients. sICAM-1 is associated with disease severity in NSTI as emphasized by significant correlations with SAPS II. Low sICAM-1 levels are an independent risk factor of 90-day mortality and appeared to give a good level of diagnostic accuracy, suggesting that sICAM-1 can be used as a prognostic biomarker for NSTI.