To understand how neutrophils are recruited to the lung in pneumococcal pneumonia, the ability of pneumococcal components to elicit the chemokine interleukin (IL)-8 from monolayers of cultured human type II cells was assessed. Heat-killed clinical and laboratory strains of Streptococcus pneumoniae and secreted proteins from exponentially growing pneumococci elicited significant quantities of IL-8 from A549 cells. All strains that elicited IL-8 production secreted a protein (∼90 kDa) that comigrated on SDS-PAGE with a C3-binding protein previously identified in S. pneumoniae. As little as 7 pmol of the purified 90-kDa protein readily elicited levels of IL-8 production equivalent to those obtained with 1 U of IL-1α. Supernatant proteins and heat-killed cells of an isogenic mutant that failed to produce the C3-binding protein elicited significantly less IL-8 than did supernatant proteins or heat-killed cells of the parent strain. These results implicate the C3-binding protein of S. pneumoniae in a novel pathway of pulmonary inflammation.