The genetic immunization of rodents with a plasmid coding for a Plasmodium chabaudi merozoite surface protein 1 (C terminus)-hepatitis B virus surface fusion protein (pPcMSP1₁₉-HBs) provided protection of mice against subsequent lethal challenge with P. chabaudi chabaudi PC1-infected red blood cells. The percentage of survivor mice was higher in DNA-immunized mice than in animals immunized with a recombinant rPcMSP1₁₉- glutathione S-transferase fusion protein administered in Freund adjuvant. In all mice immunized with the pPcMSP1₁₉-HBs, a Th1-specific response, including the production of anti-MSP1₁₉-specific immunoglobulins predominantly of the immunoglobulin G2a subtype and reacting almost exclusively against discontinuous epitopes, was elicited. The coinjection of Th1-type cytokine-expressing plasmids (gamma interferon, interleukin-2, and granulocyte-macrophage colony-stimulating factor) mostly abolished protection and boosting of MSP1₁₉-specific antibodies. The inclusion of a lymph node-targeting signal did not significantly increase protection. These data provide further evidence that MSP1₁₉-HBs DNA constructs might be useful as components of a genetic vaccine against the asexual blood stages of Plasmodium.