In humans, respiratory viral infections lead to increased airway responsiveness and exacerbations of asthma. In the present study, the role of interleukin-5 (IL-5) in virus-induced airway hyperresponsiveness and inflammation was examined in guinea pigs. In animals treated with control antibody, parainfluenza-3 virus significantly potentiated (219%) the histamine-induced increase in lung resistance compared with vehicle treatment. In addition, viral infection significantly increased (130 to 450%) the responsiveness of isolated tracheal segments to histamine in animals treated with control antibody. In guinea pigs treated with control antibody, the numbers of eosinophils (226%), neutrophils (1,380%), and monocytes (626%) in bronchoalveolar lavage fluid were significantly increased after viral infection. The level of major basic protein in bronchoalveolar lavage fluid was not altered after viral infection. In addition, electron microscopic examination of eosinophils in airway tissue and alveolar lumen did not point to increased degranulation after viral infection. In guinea pigs treated with antibody to IL-5 the virus-induced airway hyperresponsiveness to histamine both in vivo and in vitro was almost completely inhibited. In guinea pigs treated with anti-IL-5, viral infection significantly increased the numbers of eosinophils (234%), neutrophils (1,255%), and monocytes (617%) in bronchoalveolar lavage fluid. These data suggest that IL-5 plays an important role in airway hyperresponsiveness to histamine but not in the infiltration of eosinophils after respiratory viral infection.