Stimulation of tonsils or peripheral blood lymphocytes with either pokeweed mitogen (PWM) or interleukin-2 (IL-2) results in significant IgM production. However, the combination of PWM and IL-2 shows a synergistic IgM synthesis in tonsil cells, whereas the secretion in peripheral blood cells is diminished compared to activation with either stimulus alone. The heavy-chain isotype distribution does not significantly change in the two cell types when stimulated with either PWM, IL-2, or the combination. The Ig synthesis by tonsil cells to PWM or IL-2 drastically increases in the presence of monocytes, but the response to PWM + IL-2 together is not affected. The reason for the synergistic IgM production to PWM + IL-2 in tonsil cells is the relative lack of monocytes and the low number of T8+-suppressor cells. The decreased IgM production in peripheral blood cells after stimulation with both PWM and IL-2 is due to the presence of T8+ cells. These data show that the monocyte-dependent IL-2 production is an essential step in PWM-induced Ig secretion; the subsequent induction of the T-cell-helper signal for B-cell differentiation is determined by the balance between the strength of the stimulus for T cells and the T4/T8 ratio. Hence, these parameters should be included when the B-cell function is studied in vitro with the use of PWM and IL-2.