Pulmonary disease of unknown etiology is a potentially fatal complication in patients with lysinuric protein intolerance (LPI), an autosomal recessive disorder caused by the defective transport of cationic amino acids. Lung involvement was investigated in nine Italian LPI patients through pulmonary function tests and lung imaging studies consisting of conventional chest radiography, high-resolution computed tomography (HRCT), and perfusion and ventilation scintigraphy. One 10-yr-old patient died of severe respiratory insufficiency from alveolar proteinosis. All of the remaining patients were asymptomatic at the time of the study, although HRCT scans revealed signs of lung involvement defined by the presence of acinar nodules, inter- and/or intralobular thickening of the interstitial septa, and subpleural cysts in five of the patients. Radioisotope studies showed an uneven distribution of perfusion and ventilation, and confirmed the presence of segmental and/or diffuse pulmonary functional defects. No abnormalities of pulmonary function were evident, and answers to a questionnaire excluded primary coexisting lung disease. In patients with LPI, including those without clinical and functional impairment, HRCT and radioisotopic studies appear to be the most sensitive methods for the early diagnosis of lung disease and correct assessment of its progression.