We investigated the role of monocyte-lymphocyte interaction in the transformation of human peripheral blood lymphocytes by the mitogen concanavalin A (Con A). Human monocytes were separated from lymphocytes and were transiently exposed to Con A. The Con A-pretreated monocytes were able to subsequently bind autologus lymphocytes by a process that was selective for T cells. This interaction required the initial presence of Con A at the monocyte surface, and became independent of surface bound ligand after 72 hr. Levamisole, an agent thought to facilitate the participation of monocytes in the cellular immune response, enhanced the binding of lymphocytes to monocytes at low concentration of Con A (5--10 micrograms/ml). Levamisole did not lead to mitogen independent lymphocyte binding. The association between lymphocytes and Con A-pretreated monocytes resulted in the mitogenic transformation of lymphocytes in the absence of soluble Con A in the medium. These results suggest that, in addition to any possible soluble mediators, direct lymphocyte-monocyte contact is required for optimal mitogenic transformation. This T-cell-monocyte interaction over time becomes independent of cell-surface mitogen. The ability of levamisole to enhance this interaction may explain levamisole's capacity to stimulate lymphocyte proliferation.