In many cells systems, the cellular interaction between two or more humoral factors leads to a synergistic response in terms of cellular growth and function. In particular, the growth and differentiation of hematopoietic progenitor cells involves numerous synergistic interactions between colony-stimulating factors (CSFs) that individually stimulate hematopoiesis (granulocyte-CSF, granulocyte- macrophage-CSF, and interleukin-3 [IL-3]), as well as between these factors and other cytokines that individually have no proliferative effect on progenitor cell growth (IL-1 and IL-6). The present study investigated whether hematopoietic growth factor (HGF) synergy could be mediated by upregulation of CSF receptors. Synergistic effects on bone marrow (BM) progenitor cell colony formation, regardless of the combination of factors used, were consistently preceded by increased CSF receptor expression on highly enriched BM progenitor cells, but not on unfractionated BM cells. Induction of CSF receptors preceded detectable differentiation and did not require cell division because nocodazole, an inhibitor of mitosis, blocked CSF-mediated cell proliferation, but not receptor upregulation. Furthermore, combinations of cytokines that did not synergize also failed to affect the level of CSF receptors on BM progenitors. These results have led us to propose a model for HGF synergy whereby one mechanism of action the investigated synergistic cytokines might be the ability to induce increased expression of CSF receptors.