Studies were initiated to determine whether or not transformation of lymphocytes isolated from individuals functionally immune to malaria would be a useful tool for the identification of protective antigens derived from continuous cultures of Plasmodium falciparum. Soluble antigen preparations stimulated lymphoproliferative responses in cells isolated from immune and nonimmune individuals. To rule out the possibility that those nonspecific responses were mixed lymphocyte reactions or other, undefined stimuli due to the heterologous nature of the lymphocyte culture system, subsequent experiments were conducted using extracts from parasites cultured in erythrocytes obtained from the same donors whose lymphocytes were tested. Soluble parasite extracts from continuously cultured P. falciparum produce nonspecific lymphocyte blast transformation responses in immunologically naive individuals. Such mitogens should be identified and removed from antigen preparations before a vaccine against malaria can be developed.