The role of the spleen in resistance to infections with nonlethal Plasmodium yoelii 17x is dependent upon the genotype of the host. Thus, DBA/2 (D2) mice infected with P. yoelii 17x were not adversely affected by removal of the spleen, while splenectomized C57BL/6 (B6) or Balb/c mice failed to resolve their infections and eventually died. The levels of parasitemia were lower in splenectomized mice compared to intact controls; however, splenectomized mice became as anemic as did spleen-intact controls. Splenectomy resulted in the appearance of large aggregates of mononuclear cells in the livers of infected mice and also altered the liver/body weight ratios. These results indicate that D2 mice have a spleen-independent mechanism of clearing parasites which is lacking in B6 and Balb/c mice.