α-Calcitonin gene-related peptide (α-CGRP) is a 37 amino-acid neuropeptide that is primarily released from C-type sensory neurons. α-CGRP exerts multiple modulatory effects on immune responses and visceral organ function, but the role of exogenous α-CGRP in lipopolysaccharide (LPS)-induced acute lung injury (ALI) has remained to be elucidated. Forty-eight rats were randomized to receive continuous intraperitoneal infusion of α-CGRP (0.4 μg/kg/min) or normal saline for 30 min, followed by intratracheal injection of 0.5 mg/kg LPS or saline. There were four groups of animals: The saline-saline (S-S) group; the saline-α-CGRP (S-C) group; the LPS-saline (L-S) group and the LPS-α-CGRP (L-C) group. Mean arterial pressure and arterial blood gases were assessed prior to α-CGRP and LPS administration and every hour following LPS treatment. After 4 h, bronchoalveolar lavage was performed and used to assess total cell count and levels of tumor necrosis factor-α, interleukin-1β, intracellular cell adhesion molecule 1 and macrophage inflammatory protein 2. Lung tissue was also collected for assessing wet-to-dry (W/D) ratio, histology and Evans blue (EB) dye extravasation. Pulmonary α-CGRP concentration and α-CGRP receptor expression were also examined, and inducible cyclic adenosine monophosphate early repressor (ICER) and TNF-α mRNA expression levels were measured. Treatment with exogenous α-CGRP improved oxygenation during LPS-induced ALI. Correspondingly, histological injury, total cell count, inflammatory cytokine levels, W/D ratio and EB dye extravasation were also significantly reduced. α-CGRP receptor 1 expression was noted in pulmonary endothelial cells and alveolar macrophages and α-CGRP receptor expression levels were decreased during ALI, whereas pulmonary α-CGRP expression was continuously increased. Furthermore, exogenous α-CGRP induced upregulation of ICER during LPS-induced ALI. In conclusion, exogenous α-CGRP improved oxygenation and ameliorated lung damage in LPS-induced ALI, and these effects were associated with the upregulation of ICER.