Objectives Application of hyperbaric oxygen (HBO 2) treatment in the multidisciplinary setting of necrotising soft-tissue infection (NSTI) is debated as a considerable number of studies are of low quality with marked prognostication bias due to inadequately addressing disease severity. The objective of this study was to associate HBO 2 treatment with mortality in patients with NSTI including disease severity as a prognostic variable. Design Nationwide population-based register study. Setting Denmark. Participants Danish residents with NSTI patients between January 2011 and June 2016. Primary and secondary outcome measures Thirty-day mortality was compared between patients receiving and patients not receiving HBO 2 treatment using inverse probability of treatment weighting and propensity-score matching with predetermined variables (age, sex and weighted Charlson comorbidity score, presence of septic shock and Simplified Acute Physiology Score II (SAPS II)). Results A total of 671 NSTI patients were included with a median age of 63 (52-71), 61% male sex, 30% had septic shock and a median SAPS II of 46 (34-58). Patients who received HBO 2 treatment (n=266) were younger and had lower SAPS II, but a larger fraction had septic shock compared with patients not receiving HBO 2 treatment. Overall, all-cause 30-day mortality was 19% (95% CI 17% to 23%). The statistical models were in general acceptably balanced with covariates reaching <0.1 absolute standardised mean differences and patients receiving HBO 2 treatment were associated with lower 30-day mortality (OR 0.40, 95% CI 0.30 to 0.53, p<0.001). Conclusions In analyses using inverse probability of treatment weighting and propensity score analysis, patients treated with HBO 2 treatment were associated with improved 30-day survival.