Pneumolysin (PLY), a toxin synthesized by Streptococcus pneumoniae is an important virulence factor in pneumococcal disease. This study evaluated the effects of PLY in lungs of mice. Intranasal inoculation with PLY was associated with a dose-dependent influx of polymorphonuclear leukocytes (PMNL) in bronchoalveolar lavage fluid (BALF) and increased concentrations of interleukin (IL)–6, macrophage inflammatory protein (MIP)–2, and KC in BALF. PLY mutants with either reduced cytolytic activity or reduced cytolytic and complement-activating activities were less potent in inducing PMNL recruitment to the lung (P<.05), which suggests that PLY cytolytic activity is very important for the inflammatory response. IL-6 and MIP-2 also played a role in PLY-induced PMNL recruitment; this response was partially diminished in IL-6 gene–deficient mice and in mice treated with anti–MIP-2 antiserum. PLY may play an important role in the induction of an inflammatory response in the pulmonary compartment in the early phase of pneumococcal pneumonia