Rationale: Concomitant smoke inhalation trauma in burn patients represents a serious medical problem. Previous investigations in our sheep model revealed that these injuries lead to significant airway hyperemia, enhanced pulmonary fluid extravasation and severely impaired pulmonary function. However, the pathophysiologic mechanisms are still not fully understood. The lung is innervated by sensory nerves containing peptides as their neurotransmitters such as substance P and calcitonin gene-related peptide. Noxious stimuli in the airways can induce a neurogenic inflammatory response, which has previously been implicated in several diseases including allergy and asthma. In particular, calcitonin gene-related peptide is a potent vasodilator. Objective: We hypothesized that calcitonin gene-related peptide is also a mediator of the pulmonary reaction to toxic smoke. Methods: We tested the effects of pre-treatment with a specific antagonist (BIBN4096BS; 32 µg/kg, followed by continuous infusion of 6.4 µg/kg/h) in an established ovine model of burn (40% total body surface, 3^rd degree) and smoke inhalation (48 breaths, <40°C) injury. Results: In treated animals (n=7), the injury-related increases in tracheal blood flow and lung lymph flow were significantly attenuated as compared with untreated controls (n=5). Furthermore, the treatment significantly improved respiratory gas exchange. Conclusions: The data suggest that early airway hyperemia due to calcitonin gene-related peptide contributes to transvascular fluid flux and pulmonary failure following ovine burn and smoke inhalation injury. Future studies will have to clarify the potential therapeutic benefit for patients with this injury.