CD4⁺ T-cell-dependent acquired immunity confers antibody-independent protection against pneumococcal colonization. Since this mechanism is poorly understood for extracellular bacteria, we assessed the antigen specificity of the induction and recall of this immune response by using BALB/c DO11.10Rag^−/− mice, which lack mature B and T cells except for CD4⁺ T cells specific for the OVA^323-339 peptide derived from ovalbumin. Serotype 6B Streptococcus pneumoniae strain 603S and unencapsulated strain Rx1ΔlytA were modified to express OVA^323-339 as a fusion protein with surface protein A (PspA) (strains 603OVA¹ and Rx1ΔlytAOVA¹) or with PspA, neuraminidase A, and pneumolysin (Rx1ΔlytAOVA³). Whole-cell vaccines (WCV) were made of ethanol-killed cells of Rx1ΔlytA plus cholera toxin (CT) adjuvant, of Rx1ΔlytAOVA¹ + CT (WCV-OVA¹), and of Rx1ΔlytAOVA³ + CT (WCV-OVA³). Mice intranasally immunized with WCV-OVA¹, but not with WCV or CT alone, were protected against intranasal challenge with 603OVA¹. There was no protection against strain 603S in mice immunized with WCV-OVA¹. These results indicate antigen specificity of both immune induction and the recall response. Effector action was not restricted to antigen-bearing bacteria since colonization by 603S was reduced in animals immunized with vaccines made of OVA-expressing strains when ovalbumin or killed Rx1ΔlytAOVA³ antigen was administered around the time of challenge. CD4⁺ T-cell-mediated protection against pneumococcal colonization can be induced in an antigen-specific fashion and requires specific antigen for effective bacterial clearance, but this activity may extend beyond antigen-expressing bacteria. These results are consistent with the recruitment and/or activation of phagocytic or other nonspecific effectors by antigen-specific CD4⁺ T cells.