The interaction between pokeweed mitogen (PWM) and peripheral blood mononuclear cells (PBMC) was investigated using rabbit anti-PWM antiserum (anti-PWM) and 125I-PWM. Incubation of PBMC with PWM in the presence of anti-PWM resulted in an inhibition of the mitogenic effect of PWM. Anti-PWM predominantly blocked the interaction of PWM with monocytes, which is essential for optimal stimulation of lymphoid cells with PWM. Addition of anti-PWM to PBMC at several time-points after incubation with PWM showed inhibition of mitogenic activity when anti-PWM was added within 8 hours. However, enhancement of PWM-induced blast cell formation was found when anti-PWM was added after 48 hours. Further analysis revealed that the inhibition of PWM stimulation was mediated by the F(ab')2 part of anti-PWM IgG. On the other hand F(ab')2-anti-PWM was not able to enhance the effect of PWM. Incubation of PBMC with 125I-PWM and anti-PWM simultaneously, decreased the binding of PWM to both lymphocytes and monocytes. In contrast, addition of anti-PWM 48 hours after the incubation of PBMC with PWM resulted in an increased binding of PWM to monocytes. These results show that anti-PWM can modulate the lymphocyte reaction to PWM and suggest two possible mechanisms by which PWM can stimulate PBMC, both of which are dependent on the interaction of PWM with monocytes.