Immunity to "reinfection malaria" or "premunition" was studied in B-cell-deficient mice which had previously experienced acute malaria caused by the avirulent plasmodia Plasmodium yoelii or P. chabaudi or by the lethal P. vinckei. Such mice resisted challenge infection with large numbers of homologous parasites but differed in their capacity to resist challenge with heterologous species. Mice immune to P. yoelii resisted infection with P. chabaudi but developed acute-type, albeit nonlethal, infections when challenged with P. vinckei. Whereas mice immune to P. chabaudi resisted challenge with P. vinckei and vice versa, they developed fulminating malaria and died when infected with P. yoelii. The data suggest that immunity to reinfection malaria in B-cell-deficient mice, although antibody independent, is mediated by different mechanisms of resistance depending upon the plasmodial species used to initiate acute infection. Additional evidence supporting this concept was gained from preliminary experiments in which immunity to reinfection was measured by the ability of chronically infected mice to control endogenous parasites at low levels. B-cell-deficient mouse strains showed genotypic differences in their ability to develop immunity to reinfection with P. yoelii. In contrast, the same mouse strains uniformly developed immunity to reinfection with P. chabaudi. These findings suggest that different genetic loci control resistance to reinfection malaria caused by different species of plasmodia. Finally, B-cell-deficient mice acutely infected with lethal plasmodia, P. vinckei or P. berghei, died at the same time or earlier than similarly infected immunologically intact mice, indicating that "early death" in virulent malarial infections is an antibody-independent phenomenon.