Cultured mast cells derived from murine bone marrow were investigated for the presence of specific interferon-gamma (IFN-gamma) receptors, and for the effects of IFN-gamma on mast cell proliferation. 125I-labeled recombinant IFN-gamma (125I-Mu-rIFN-gamma) was shown to bind to high-affinity receptors on these cells. Scatchard analysis of binding data indicated the presence of about 500 homogeneous binding sites per cell, with an apparent equilibrium dissociation constant of 3 X 10(-10) M. The binding of 125I-Mu-rIFN-gamma to mast cells was inhibited by unlabeled Mu-rIFN-gamma but not by unlabeled Mu-IFN-alpha/beta. Cross-linking of 125I-Mu-rIFN-gamma to mast cell membrane proteins using a cross-linking agent yielded a predominant complex of 100 +/- 10 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography which most likely represents the IFN-gamma-receptor complex. To assess the biological significance of these receptors, we studied the effects of Mu-rIFN-gamma on mast cell proliferation, which was markedly inhibited in mast cell precursors but not in mature mast cells. These in vitro results are in agreement with the antiproliferative effect of IFN-gamma previously reported for other hematopoietic progenitors, and suggest that IFN-gamma could find its application in the treatment of human systemic mastocytosis.