Immunity to pneumococcal colonization in mice by exposure to live or killed pneumococci has been shown to be antibody independent but dependent on CD4 + T cells. Here we show that intranasal immunization with pneumococcal proteins (pneumococcal surface protein C, adhesin A, and a pneumolysoid) can elicit a similar mechanism of protection. Colonization could be significantly reduced in mice congenitally deficient in immunoglobulins after intranasal immunization with this mixture of proteins; conversely, the depletion of CD4+ T cells in immunized wild-type mice at the time of challenge eliminated the protection afforded by immunization. Overall, our results show that intranasal immunization with a mixture of pneumococcal proteins protects against colonization in an antibody-independent, CD4 + T-cell-dependent manner. Copyright © 2007, American Society for Microbiology. All Rights Reserved.