ABSTRACT Immunity induced by the 19-kDa fragment of Plasmodium yoelii merozoite surface protein 1 (MSP1 ₁₉ ) is dependent on high titers of specific antibodies present at the time of challenge and a continuing active immune response postinfection. However, the specificity of the active immune response postinfection has not been defined. In particular, it is not known whether anti-MSP1 ₁₉ antibodies that arise following infection alone are sufficient for protection. We developed systems to investigate whether an MSP1 ₁₉ -specific antibody response alone both prechallenge and postchallenge is sufficient for protection. We were able to exclude antibodies with other specificities, as well as any contribution of MSP1 ₁₉ -specific CD4 ⁺ T cells acting independent of antibody, and we concluded that an immune response focused solely on MSP1 ₁₉ -specific antibodies is sufficient for protection. The data imply that the ability of natural infection to boost an MSP1 ₁₉ -specific antibody response should greatly improve vaccine efficacy.