Clinical trials with partial liquid ventilation demonstrate improvement in oxygenation, as well as some adverse side effects linked to the application of liquid perfluorocarbons (PFCs) during liquid ventilation. Thus, we examined the effects of systemic administration of PFC on acute lung injury (ALI) induced by lipopolysaccharide (LPS) and its effects on heme oxygenase-1 (HO-1), a compound that provides potent cytoprotection against lung injury. Rats were assigned to one of six groups (n = 8). Thirty minutes after they were challenged with LPS aerosol inhalation, perfluorohexane was given intraperitoneally every two hours. Ten hours after LPS inhalation, bronchoalveolar lavage fluid (BALF) and lung tissue were obtained for enzyme linked immunosorbent assay, histologic, and Western-blot analyses. The results showed that perfluorohexane significantly decreased the wet to dry weight ratio, malondialdehyde (MDA) production, and myeloperoxidase (MPO) activity in the lung tissue. Also, perfluorohexane reduced the total protein content and levels of tumor necrosis factor-alpha (TNF-alpha) but increased the levels of the anti-inflammatory cytokine interleukin-10 (IL-10) in the BALF, resulting in decreased pulmonary edema and the infiltration of neutrophils into the lung tissues of LPS-treated rats. Furthermore, perfluorohexane increased HO-1 protein production and stimulated HO-1 activity in the lung tissue. Pre-treatment with Zinc protoporphyrin IX, an inhibitor of HO-1, decreased the protective effects of perfluorohexane in rats. In summary, systemic perfluorohexane alleviates LPS-induced lung injury in rats, and HO-1 may be involved in the mechanism of this reduction.