The spleen plays a central role in host defense against malaria in animals. Its role in human malaria is less well established. The spleen may contribute to protection against human malaria by mediating humoral or cellular immune responses or by clearing both rheologically and immunologically altered host erythrocytes. This report describes Plasmodium falciparum and Plasmodium vivax infections that occurred after splenectomy in one nonimmune and three partially immune Thai adults. The clinical course was uncomplicated for all four patients, and parasite clearance was delayed only in the nonimmune patient. In three patients with falciparum malaria, humoral and cellular immune responses to blood-stage antigens during the acute infection and convalescence were similar to those of individuals whose spleens were intact. These findings suggest that the spleen may not be essential for the processes leading to parasite clearance in partially immune, splenectomized patients. Further studies on the course of malarial infections in splenectomized patients are crucial for clarifying the role of the spleen in host defense against human malaria.