An experimental model of pneumococcal bacteremia in guinea pigs has been developed. By use of this model, complement has been shown to play a critical role in clearance of Streptococcus pneumoniae from the bloodstream and in survival of guinea pigs after iv challenge with type 7 S. pneumoniae. In nonimmune animals, complement activation occurs primarily via the alternative pathway. However, anticapsular antibodies increase the rate of clearance of pneumococci primarily via activation of the classical complement pathway. Detailed studies of the reticuloendothelial localization of cleared radiolabeled pneumococci showed that clearance took place primarily in liver and spleen and that anticapsular antibody increased hepatic and decreased splenic sequestration. This effect could be blocked by depleting complement with cobra venom factor. Comparison of nonimmune animals injected with unencapsulated pneumococci or encapsulated types 7 or 12 pneumococci showed that the virulence of these organisms for guinea pigs correlated with the extent of splenic sequestration. Sensitization of encapsulated pneumococci with anticapsular antibodies led to an antibody dose-dependent increase in the rate of bloodstream clearance. Sensitization of encapsulated pneumococci with anticell wall antibodies had no effect on clearance rates despite the ability of these antibodies to bind to the bacteria and to activate and fix complement to the organisms. In vitro studies showed that C3b deposited by these opsonically ineffective antibodies interacted poorly with C3b receptors. Electron microscopic studies showed that C3b deposited by anticapsular antibodies bound to the pneumococcal capsule while C3b deposited by anti-cell wall antibodies did not. Thus, the localization of C3b deposition on the pneumococcus markedly affects its opsonic potential.