Elevated lymphoproliferative responses following in vivo inoculation of sublethal doses of mouse plasma cell tumors were detected by a mixed lymphocyte-tumor interaction (MLTI) assay. Specificity of elevated MLTI responses correlated with resistance to in vivo tumor challenge. These responses were dependent upon the presence of thymus-derived cells. Spleen and lymph node cells showed markedly different patterns of MLTI activity following plasma cell tumor immunization. Spleen cell responses were depressed for the first 30 days postimmunization, but lymph node cells showed augmented MLTI reactivity immediately after immunization. Lymphocyte populations from different lymphoid organs may show widely dissimilar responses in vitro at the same point in the in vivo development of tumor resistance.