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Purpose Necrotising soft tissue infection (NSTI) is a deadly disease associated with a significant risk of mortality and long-term disability from limb and tissue loss. The aim of this study was to determine the effect of hyperbaric oxygen (HBO 2) therapy on mortality, complication rate, discharge status/location, hospital length of stay and inflation-adjusted hospitalisation cost in patients with NSTI. Methods This was a retrospective study of 45,913 patients in the Nationwide Inpatient Sample (NIS) from 1988 to 2009. Results A total of 405 patients received HBO 2 therapy. The patients with NSTI who received HBO 2 therapy had a lower mortality (4.5 vs. 9.4%, p= 0.001). After adjusting for predictors and confounders, patients who received HBO 2 therapy had a statistically significantly lower risk of dying (odds ratio (OR) 0.49, 95% confidence interval (CI) 0.29–0.83), higher hospitalisation cost (US 52,205vs.US 45,464, p= 0 …