A number of blood-stage malaria Ags are under development as vaccine candidates, but knowledge of the cellular responses to these vaccines in humans is limited. We evaluated the nature and specificity of cellular responses in healthy American volunteers vaccinated with a portion of the major merozoite surface protein-1 (MSP1) of Plasmodium falciparum, MSP142, formulated on Alhydrogel. Volunteers were vaccinated three times with 80 μg of either MSP142-FVO/Alhydrogel or MSP142-3D7/Alhydrogel. Cells collected 2 wk after the third vaccination produced Th1 cytokines, including IFN-γ and IL-2 following Ag stimulation, and greater levels of the Th2 cytokines IL-5 and IL-13; the anti-inflammatory cytokine IL-10 and the molecule CD25 (IL-2Rα) were also detected. The volunteers were evaluated for the MSP142-FVO or MSP142-3D7 specificity of their T cell responses. Comparison of their responses to homologous and heterologous Ags showed ex vivo IFN-γ and IL-5 levels that were significantly higher to homologous rather than to heterologous Ags. The epitopes involved in this stimulation were shown to be present in the dimorphic MSP133 portion of the larger MSP142-3D7 polypeptide, and indirect experiment suggests the same for the MSP142-FVO polypeptide. This contrasts with B cell responses, which were primarily directed to the conserved MSP1 19 portion. Furthermore, we explored the maturation of memory T cells and found that 46% of vaccinees showed specific memory T cells defined as CD42+CD45RO2+CD40L2+ after long-term in vitro culture. The identification of human-specific CD42+ memory T cells provides the foundation for future studies of these cells both after vaccination and in field studies.