Retrovirally mediated introduction of a cDNA encoding a placenta-derived low-affinity receptor for human granulocyte-macrophage colony-stimulating factor (GM-CSF) into murine FDC-P1 hemopoietic cells allowed these cells to proliferate when stimulated by human GM-CSF. The expressed human receptors on cloned lines were of low affinity (Kd = 4-6 nM), were internalized, and did not interact with endogenous GM-CSF receptors. Concentrations of human GM-CSF of 6.5-13 nM were required to stimulate 50% maximal colony formation versus a concentration of murine GM-CSF of 6 pM; this difference is comparable with the difference in relative affinities of the human and murine receptors for their respective ligands. If maintained in murine GM-CSF, cells able to bind or respond to human GM-CSF were rapidly lost due to transcriptional inactivation of the inserted cDNA. The observations indicate that low-affinity receptors for human GM-CSF can deliver a proliferative signal in appropriate cells and that the signaling mechanisms are not species-specific.