Invasive infections by encapsulated bacteria are the major cause of human morbidity and mortality. The liver resident macrophages, Kupffer cells, form the hepatic firewall to clear many encapsulated bacteria in the blood circulation but fail to control certain high-virulence capsule types. Here we report that the spleen is the backup immune organ to clear the liver-resistant serotypes of Streptococcus pneumoniae (pneumococcus), a leading human pathogen. Asplenic mice failed to control the growth of the liver-resistant pneumococci in the blood circulation. Immunologic and genetic analyses identified splenic red pulp (RP) macrophages as the major phagocytes for bacterial clearance. Furthermore, the plasma natural antibodies against the cell wall phosphocholine and the complement system were necessary for RP macrophage-mediated immunity. These findings have provided a conceptual framework for the innate defense against blood bacterial infections, a mechanistic explanation for the hyper-susceptibility of asplenic individuals to S. pneumoniae, and a proof of concept for developing vaccines and therapeutic antibodies against encapsulated pathogens.