Using a rabbit model of experimental pneumonitis, the components on the surface of the pneumococcus that incite pulmonary inflammation were identified. Rabbits were challenged intratracheally with live pneumococci, capsular polysaccharide, purified cell walls, or cell wall subcomponents. Leukocytosis and elevation of protein concentration was quantitated in bronchial lavage fluid during the first 24 h after challenge. Of the pneumococcal surface components tested, cell wall preparations had the highest specific activity in inducing inflammation; abnormalities in bronchial lavage fluid cytochemistry appeared rapidly and in a dose-dependent manner. Cell wall building blocks and the products of penicillin-induced hydrolysis of the cell wall were also highly inflammatory, indicating that inflammation can be generated by disruption of the cell wall during lysis of bacteria by beta-lactam antibiotics. Administration of inhibitors of arachidonic acid metabolism suggested that inhibition of the lipoxygenase pathway reduced inflammation associated with cell walls. We propose that pulmonary inflammation during pneumococcal pneumonia arises in large part from the interaction of the bacterial cell wall with complement and noncomplement-mediated host defenses.