Recent investigations have shown that guinea pigs are important for the study of influenza A virus (IAV) transmission. However, very little is known about IAV replication and histopathology in the guinea pig respiratory tract. Here, we describe viral growth kinetics, target cells and histopathology in the nasosinus, trachea and lungs of IAV-infected guinea pigs. We found that guinea pigs infected with either A/Puerto Rico/8/34 (H1N1) or A/Hong Kong/8/68 (H3N2) developed a predominantly upper airway infection with high nasal viral titres. IAV grew to moderate titres in the lungs but induced marked inflammatory responses, resulting in severe bronchopneumonia and alveolitis. Although non-lethal at the high dose of 2x10(6) p.f.u., infections with these IAV strains were associated with reduced weight gain. IAV infection in guinea pigs is characterized by extensive viral replication in the ciliated nasal epithelial cells followed by heavy nasal mucus secretion.