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A global pandemic influenza A (H1N1) outbreak occurred in 2009. Rapid progress of respiratory distress is one of the characteristic features of pandemic influenza A (H1N1) infection. The physiologic mechanism causing hypoxia in pandemic influenza A (H1N1) infection, however, has not been elucidated.The serum levels of KL–6 and surfactant protein D (SP–D) were evaluated in 21 cases of pandemic influenza A (H1N1) infection associated with chest radiographic abnormality in order to estimate alveolar involvement. The clinical features were also analyzed.All of the patients had high fever, and rapidly progressed to respiratory distress within several days of disease onset. Despite mild radiographic abnormality in these patients, dyspnea was severe and they had low blood oxygen saturation levels. Many of the patients had a history of allergic diseases including asthma. Serum KL–6 and SP–D levels on admission were 191 ± 69 U/mL and 32.6 ± 18.9 ng/mL, respectively. These two levels were still below the upper normal limit 1 week later. There were no clear relationships between specific clinical symptoms and KL–6 or SP–D levels. All patients were treated with oseltamivir and/or zanamivir, and improved without mechanical ventilation management.KL–6 and SP–D elevation were not significant in pandemic influenza A (H1N1) infection associated with chest radiographic abnormality. In pandemic influenza A (H1N1) infection, alveolar involvement was estimated to be little, and severe respiratory distress was probably caused by obstruction of peripheral bronchi.