It has recently become apparent that inflammatory reactions including nitric oxide (NO) release contribute to the outcome of pulmonary infections. To investigate the effect of N^G-monomethyl-L-arginine (L-NMMA), a NO synthase inhibitor, on the pathogenesis of pneumococcal pneumonia, we inoculated CD₁ Swiss mice with 10⁷ CFU of Streptococcus pneumoniae. Treatment with two daily subcutaneous injections of 3 mg of L-NMMA per kg of body weight (over a 5-day period) reproducibly delayed mortality, as the number of surviving mice 72, 84, and 96 h after infection was increased by 16.8% (P < 0.05), 25.0% (P < 0.005), and 11.5% (P < 0.05), respectively. In fact, the following chronology of events was noted in L-NMMA-treated infected animals, compared to the untreated infected controls. (i) At 12 to 24 h after infection, larger amounts of leukotriene B₄ in bronchoalveolar lavage (BAL) fluid associated with greater neutrophilia in lung tissue and alveolar spaces and more persistent release of tumor necrosis factor alpha, interleukin-1 alpha (IL-1), and IL-6 were observed. (ii) At 24 to 72 h, there was better preservation of lung ultrastructure, including reduction of edema in the interstitium and protection of alveolar spaces, despite identical bacterial growth in lungs, in L-NMMA-treated infected animals than in untreated animals. (iii) At 72 to 96 h, the death rate was delayed, despite the absence of antibiotic therapy. In our experiment, partial blockade of NO release was achieved. These data indicate that NO plays an important role in the induction of tissue injury and death during pneumococcal pneumonia and that L-NMMA is helpful for host protection.