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To determine whether the combination of aerosolized unfractionated heparin and N-acetylcystine reduces 28-days mortality and lung injury scores (LISs) in adult patients with smoke inhalation injury requiring mechanical ventilation. The study was a single-center retrospective study with historical control. The authors included 30 mechanically ventilated adult subjects who were admitted within 48 hours of their bronchoscopy confirmed smoke inhalation injury over a 5-year period. The experimental group was treated with nebulized heparin sulfate, N-acetylcystine, and albuterol sulfate. Controls received ventilation support and albuterol sulfate. The authors calculated acute physiology and chronic health evaluation (APACHE)-III scores on admission in addition to daily LIS for 7 days. The experimental group was divided into five APACHE-III subgroups and matched with inhalation lung injury patients in the historical control group. There was no significant difference in initial APACHE-III scores or LISs between groups (α = 0.05) upon entry to the study. The experimental group showed significant improvement in LISs, respiratory resistance and compliance measurements, and hypoxia scores as compared with controls throughout the duration of the study. There was a statistically significant survival benefit in the experimental group that was most pronounced in patients with APACHE-III scores >35. Survival for the control vs experimental group was 0.5714 ± 0.1497 vs 0.9375 ± 0.0605, respectively, (risk ratio −0.0055; 95% confidence interval −0.0314-0.0204; hazard ratio 1.003; number needed to treat 2.7). The use of aerosolized unfractionated heparin and N−acetylcystine attenuates lung injury and the progression of acute respiratory distress syndrome in ventilated adult patients with acute lung injury following smoke inhalation.