Smoke inhalation injury (SII) is associated with significant morbidity and mortality in burn patients, and effective treatments are lacking. Perfluorocarbons (PFCs) have a protective effect against acute lung injury. We aimed to assess the therapeutic effects of perfluorohexane on burn patients with SII. Patients with burns complicated by moderately severe SII were randomly divided into control (n = 11) and PFC groups (n = 12). The control group received conventional treatment (anti-infection, nutritional support, antishock measures, and supportive treatment). The PFC group received endotracheal perfluorohexane instillation in addition to conventional treatment. On admission and 3 days later, therapeutic effects were evaluated and inflammatory mediators in bronchoalveolar lavage fluid and plasma were analyzed. There was no significant difference between the control and PFC group on admission. After 3 days, perfluorohexane treatment significantly (P < .05) increased lung dynamic compliance, and reduced alveolar-arterial oxygen gradient, Acute Physiology and Chronic Health Evaluation II score, percentage of neutrophils, and levels of interleukin-6, interleukin-8, and tumor necrosis factor alpha in bronchoalveolar lavage fluid; there was no significant change in the control group before and after treatment. Intratracheal instillation of perfluorohexane modulates the pulmonary immune microenvironment and supplements current conventional treatments for burn patients with SII.