Inhalation injury (IHI) causes significant morbidity and mortality in burn victims due to both local and systemic effects. Nebulized heparin promotes improvement in lung function and decreased mortality in IHI by reducing the inflammatory response and fibrin cast formation. The study objective was to determine if nebulized heparin 10,000 units improves lung function and decreases mechanical ventilation duration, mortality, and hospitalization length in IHI with minimal systemic adverse events. This retrospective, case-control study evaluated efficacy and safety of nebulized heparin administered to mechanically ventilated adults admitted within 48 hr of confirmed IHI. Nebulized heparin 10,000 units was administered Q4H for 7 days, or until extubation if sooner, alternating with albuterol and a mucolytic. Patients were matched on a case-by-case basis based on percent TBSA burn and age to patients from a historical group with IHI before heparin protocol implementation. The primary outcome was duration of mechanical ventilation. Secondary outcomes included lung injury score, ventilator-free days during the first 28 days, 28-day mortality, hospitalization length, ventilator-associated pneumonia incidence, bronchoscopy incidence, and bleeding events. Data were collected in 72 patients, 36 of which received nebulized heparin and 36 historical controls. Two patients from the heparin group and three patients from the control group died/were discharged while on the ventilator. Data were analyzed separately with 1) all subjects included and 2) with subjects who died/were discharged on the ventilator excluded. In the latter comparison, patients receiving nebulized heparin demonstrated a statistically significant decrease in median (interquartile range) duration of initial mechanical ventilation compared with controls [7.0 (4.0, 13.5) vs. 14.5 (5.3, 22.3) days; P = .044]. Patients in the heparin group had a significantly increased number of median (interquartile range) ventilator-free days in the first 28 days [21.0 (14.5-24.0) vs 13.5 (4.3-22.8) days; P = .031]. There were no differences in hospitalization length, lung injury score during the first 7 days post injury, 28-day mortality, ventilator-associated pneumonia rate, or bleeding events. Nebulized heparin 10,000 units in conjunction with a beta-agonist and mucolytic produced a significant decrease in duration of mechanical ventilation and increase in ventilator-free days in adult patients with IHI. Nebulized heparin was safe and did not result in an increase in bleeding events. To our knowledge, this is the first case-control study with matched cohorts based on age and %TBSA which are significant factors contributing to morbidity and mortality in IHI.