Infection with influenza A (H5N1) virus, which has not been associated with respiratory disease in humans previously, caused clinical signs of acute respiratory distress syndrome and multiple-organ dysfunction syndrome with high mortality in humans in Hong Kong in 1997. To study the pathogenesis of this disease, we infected four cynomolgus monkeys (Macaca fascicularis) with 2.5 x 104 median tissue culture infectious dose (TCID50) of influenza virus A/Hong Kong/156/97 (H5N1) and euthanatized them 4 or 7 days after infection. The main lesion was a necrotizing broncho-interstitial pneumonia (4/4) similar to those found in primary influenza virus pneumonia in humans, with desquamation of respiratory epithelium (4/4), intra-alveolar hemorrhage (4/4), hyaline membrane formation (2/4), and infiltration with neutrophils and macrophages (4/4). Lesions in other organs consisted of a suppurative tonsillitis (2/4) and necrosis in lymphoid organs (1/4), kidney (1/4), and liver (1/4). By immunohistochemistry, influenza virus antigen was limited to pulmonary tissue (4/4) and tonsils (2/4). Based on these results, we suggest that the cynomolgus monkey is a suitable animal model for studying the pathogenesis of human H5N1 virus infection and that multiple-organ dysfunction syndrome in this disease may be caused by diffuse alveolar damage from virus replication in the lungs alone.