Normal CD-1 mice were inoculated intratracheally with Streptococcus pneumoniae and treated with aspirin in order to assess the effects of that drug on pulmonary antibacterial mechanisms. Animals pretreated for 72 h with aspirin prior to bacterial challenge and animals given aspirin immediately after infection experienced worse survival rates than did control mice (p less than 0.01 and p less than 0.05, respectively). When challenged with a sublethal inoculum, pretreated and immediately treated animals demonstrated significant impairments in their ability to clear viable pneumococci from the lungs; the inefficient pulmonary clearance was associated with a marked attenuation in the ability of aspirin-treated mice to recruit granulocytes and macrophages into the bronchoalveolar spaces. Survival in mice administered aspirin 6 h after pneumococcal challenge was not adversely affected; however, the pulmonary clearance and cellular response were significantly impaired. We conclude that aspirin can disrupt host defense against pneumococci by blunting the normal pulmonary inflammatory reaction to organisms deposited into the lower respiratory tract.