The blastogenic response of normal spleen, lymph node, and peripheral blood lymphoid cells to tumor-associated antigens (TAA) derived from two syngeneic C57BL/6J tumors was measured by [3H]thymidine incorporation. Peripheral blood cells were responsive to TAA from B16 melanoma and from BW10232 mammary carcinoma at both a high (10(-1) to 10(-3) mg/ml) and a low (10(-5) to 10(-6) mg/ml) concentration of antigen. While peripheral blood cells always responded to TAA, spleen cells and lymph node cells did not. When spleen and lymph node cells did respond, they sometimes responded at different concentrations of TAA than did the peripheral blood cells. Spleen cells generally responded to "low" concentrations of TAA, while lymph node cells responded to "high" concentrati-ns of TAA. These data suggest two subpopulations of lymphoid cells capable of response to TA.. Spleen cells from mice bearing the BW10232 mammary carcinoma became responsive to BW10232 TAA at low concentrations of antigen. Lymph node cells became responsive at high concentrations of BW10232 antigen. The response of both subpopulations to BW10232 TAA was amplified in peripheral blood cells. Spleen cells were 30 times more responsive in the tumor bearer than in normal animals, while lymph node cells were only 3 times more responsive. It is shown that lymphoid cells taken from different areas or "lymphoid compartments" do not always show similar responses and should not be considered equivalent in evaluating immune responses to tumor cells.