The merozoite surface protein-1 (MSP1) of Plasmodium falciparum possesses intervening conserved and nonconserved sequences. The relative importance of these sequences in providing T cell help for Ab production was investigated in a series of cross-priming studies using homologous and heterologous parasite MSP1 proteins. Cross-priming with heterologous MSP1s was as efficient as homologous immunizations in inducing anti-MSP1 Abs. Similar to homologous immunization, cross-priming with heterologous MSP1s induced primarily Abs to conserved epitopes. The specificities of the Abs were also similar for the two immunization regimens. Studies were also performed with use of the C-terminal p42 fragment of MSP1 expressed in baculovirus (BVp42). When BVp42 was used either as the priming Ag followed by boosting with homologous (or heterologous) MSP1 or as the booster Ag after priming with homologous (or heterologous) MSP1, much lower anti-BVp42 Ab titers were produced compared with priming/boosting with homologous or heterologous MSP1s or BVp42 alone. Thus, immunization with the complete parasite MSP1 induced a dominant, conserved Th epitope(s) specific for anti-p42 Ab production, and such determinant(s) was either located outside the p42 region or was not provided by the BVp42 because of possible differences in the processing of parasite MSP1 vs BVp42. Our data provided a strong rationale to identify and include conserved Th epitope(s) in MSP1 vaccines. Furthermore, a MSP1 vaccine on the basis of the C-terminal p42 fragment may benefit by the inclusion of additional Th epitopes to achieve effective boosting in the field.