Activated T-lymphocytes secrete interleukin-4 (IL-4), which has been shown to modulate a variety of monocyte activities requiring monocyte/macrophage colony-stimulating factor (M-CSF). To account for this interaction, we postulated that IL-4 acts on target cells by altering the expression of the M-CSF receptor (M-CSFr). To test this hypothesis, murine bone marrow macrophages were cultured under conditions that down-regulate M-CSFr and the effect of IL-4 on the reexpression of the receptor measured by binding of 125I-labeled M-CSF to the cells. The data show that incubation with IL-4 results in a dose-dependent, 2-3 x increase in M-CSFr with no change in binding affinity and a maximal effect on binding at about 12 h. This increase in M-CSFr is dependent upon new, specific protein synthesis as shown by the inhibitory action of cycloheximide, and gel analysis of radiolabeled, specific protein, immunoprecipitated with anti-M-CSFr antibody. Treatment with IL-4 does not stimulate M-CSFr mRNA expression but, consistent with enhanced receptor levels, does result in a heightened proliferative response to M-CSF. Thus, IL-4 affects M-CSF treated monocytic cells, at least in part, by altering the expression of M-CSFr.