The response of lymphocyte subpopulations to pokeweed mitogen (PWM) was studied in normal volunteers and patients with B-cell chronic lymphocytic leukemia (CLL). Since unfractionated peripheral blood mononuclear (PBM) cells from CLL patients consist of a markedly increased proportion of B-lymphocytes and a decreased proportion of T-lymphocytes, enriched fractions of CLL B-cells and CLL T-cells were cultured in 1:1 proportions in autologous and allogeneic combinations with normal B-cell and T-cell-enriched fractions. Cultures containing normal B-cells with either autologous or allogeneic normal T-cells responded well to PWM. CLL T-cells were capable of providing a helper function for both proliferation and differentiation of normal B-cells, which was not significantly different from that provided by allogeneic normal T-cells. CLL B-lymphocytes were unresponsive to PWM when cultured in the presence of either autologous CLL T-lymphocytes or allogeneic normal T-lymphocytes. The responsiveness of CLL B-cells was not restored by the addition of normal peripheral blood monocytes to the cultures. These experiments indicate that there is an intrinsic B-cell defect which prevents CLL B-lymphocytes from responding to PWM.