The C-terminal 42 kDa fragment (MSP1-42) and its smaller 19 kDa subfragment (MSP1-19) of the Plasmodium falciparum merozoite surface protein, MSP1, are leading candidate malaria vaccines. Since the targets of protective immunity lie within the MSP1-19, we compared the anti-MSP1-19 antibodies induced by vaccination with recombinant MSP1-42 and MSP1-19. The specificities of the antibody responses were analyzed using five recombinant MSP1-19s expressing different naturally occurring variant amino acid residues. We observed dramatic differences in the specificities of the anti-MSP1-19 antibodies induced by the two vaccines. MSP1-42 consistently induced crossreactive antibodies; whereas the antibodies induced by recombinant MSP1-19 were highly variable among animals in terms of recognition of conserved versus variant epitopes. Of the variant residues examined, only a subset significantly contributed as part of immunogenic B epitopes. MSP1-42 consistently induced potent growth inhibitory antibodies that recognized conserved epitopes, leading to efficient inhibition of heterologous parasites. In contrast, MSP1-19 induced strong inhibitory antibody responses in only a subset of animals studied. In some of the MSP1-19 immunized animals, inhibition of homologous parasites may be due to recognition of inhibitory epitopes associated with the homologous variant residues, and the induction of antibodies to conserved inhibitory epitopes may not be efficiently achieved. These data suggest an advantage of using MSP1-42 over MSP1-19 based vaccines.