The antibody response to Plasmodium yoelii is altered in splenectomized mice. Sera were obtained from sham-operated or splenectomized DBA/2 and C57BL/6 mice on Days 11, 18, and 24 after infection with nonlethal P. yoelii 17x and used to precipitate metabolically radiolabeled parasite antigens. Mice of both strains responded to many antigens. However, only splenectomized DBA/2 mice made strong antibody responses to antigens of approximately 110, 56, 50, 40, 35, and 20 kDa. Metabolically radiolabeled parasite extracts prepared in sham-operated and splenectomized mice appeared identical on SDS-PAGE. Thus it is unlikely that expression of new parasite antigens in splenectomized DBA/2 mice accounts for these results. Parasite-reactive IgM and IgG antibody responses were also modulated by splenectomy. Levels of IgM increased in splenectomized DBA/2 mice and decreased in C57BL/6 mice. Both mouse strains had slight to moderate increases in IgG when infected after splenectomy. The results suggest that when the spleen is present, responses to specific antigens are markedly suppressed. Alternatively, it is possible that in the absence of a spleen, antigen processing and presentation occurs in other tissues such as the lymph nodes or liver, leading to responses that are qualitatively different than those which occur when the spleen is present.