To evaluate the potential role of viruses in the pathogenesis of hypersensitivity pneumonitis (HP), we looked at the effect of challenging normal versus Sendai-injected mice with Saccharopolyspora rectivirgula (SR). In this model of HP, mice are nasally instilled with SR antigen three consecutive days per week of study. For this study virus was given after 3 weeks of SR. Two positive (SR alone, virus alone) and a negative (saline) control groups were done in parallel with the viral plus SR group. Lung response to these different conditions was evaluated by lung index, bronchoalveolar lavage (BAL) cell populations, lung histopathology, and BAL fluid fibronectin levels. SR challenge resulted in an increase in BAL cells, lung index, and BAL fibronectin levels and in a peribronchial inflammatory reaction. The virus alone produced a transient increase in BAL cells. The cellular response to SR, in virus-injected animals, was greater than the added effects of the virus and SR. Virus alone had no persistent effect on the other measured parameters and did not change the effect of SR on these variables. We conclude that the Sendai virus enhances the cellular response of the mouse lungs to an SR antigenic challenge.