We previously reported that protection of mice from nonlethal Plasmodium yoelii malaria by immunization with whole killed blood-stage parasites was dependent on the adjuvant and that adjuvants influenced both the specificity and isotype of Ab. Additional studies with the most effective formulations were undertaken to better define the protective responses and 100% protection from lethal P. yoelii malaria was produced by three immunizations with Ag in copolymer P1004 and detoxified RaLPS as adjuvants and 83% protection was induced by a single immunization. The protection lasted for 9 mo and was associated with an anamnestic rise in Ab titer of the IgG2a isotype during the challenge infection. Passive immunization with Ab from animals that had been immunized and challenged transferred sterile immunity. Splenectomy reduced, but did not abolish, protection. These data suggest that the effective Ab is directed against labile epitopes on the surface of blood-stage parasites. The vaccines primed animals for production of such Ab, but its synthesis was efficiently induced only by challenge with live organisms.