Different mouse strains show marked variation in susceptibility to murine malaria parasites. Of those studied, strain A mice showed the highest susceptibility, most animals dying from Plasmodium chabaudi infections. In contrast, C57Bl and CBA mice all recovered from P. chabaudi infections and were then resistant to challenge with a virulent strain of P. yoelii. BALB/c mice recovered from P. chabaudi infections but were not uniformly resistant to P. yoelii challenge. B10.A mice, which share haplotypes (H-2(a)) with strain A mice, were resistant to P. chabaudi infections. Of all the correlates of resistance, one appears to be of special interest: natural killer (NK) activity. This was high in C57Bl mice and in malaria-infected mice considerable increases in spleen cell numbers and in NK activity were observed. In contrast, strain A mice showed low NK activity and in malaria-infected animals spleen cell numbers and NK activity showed little or no increase. It is suggested that NK cells, recruited and activated by T lymphocyte-mediated immune responses to parasite antigens, recruit and activate NK cells and macrophages, and that a product of the reacting cells may produce death of parasites within circulating erythrocytes.