Numerous studies have identified strategies to reduce mechanical ventilation duration by targeting appropriate sedation levels. However, applicability of these strategies to critically injured patients with burn injury has not been established. At our medical center, methadone is commonly used early in the care of burn patients to treat background pain and limit the development of opioid tolerance. The aim of this study is to evaluate the effect of early methadone initiation in critically injured burn patients requiring mechanical ventilation. This retrospective study compared patients who received early methadone with patients who did not while mechanically ventilated with the primary outcome of ventilator-free days in a 28-day period. Those who received methadone within 4 days of intubation and remained ventilated for 2 days after the first dose were included in the methadone group. Propensity scores were used to match up to three control patients to each methadone patient. Seventy patients (18 methadone and 52 matched control patients) were included in the final evaluation. Patients in the methadone group averaged 16.5 ventilator-free days compared with 11.5 in the control group (P = .03). There was no statistical difference in the duration of intensive care unit or hospital length of stay between groups. Our results suggest that early methadone initiation may have a significant effect on ventilator outcomes in critically injured patients with burn injury. However, further research is warranted.