Erythropoietin (EPO) is a hematopoietic growth factor that stimulates the proliferation and differentiation of erythroid progenitor cells. Although the EPO receptor has no kinase domain, EPO rapidly induces tyrosine phosphorylation of several proteins in EPO-responsive cells. Therefore, the receptor activation by the ligand could induce tyrosine- kinase activity of unidentified cellular protein(s). Here we show that c-fps/fes proto-oncogene product (p92c-fes), nonreceptor tyrosine kinase, is tyrosine-phosphorylated on treatment with EPO in a human erythroleukemia cell line TF-1 that is responsive to granulocyte- macrophage colony-stimulating factor, interleukin-3, and EPO. In addition, the kinase activity of p92c-fes was shown to be enhanced by treatment with EPO. Therefore, p92c-fes could be implicated in a signaling pathway triggered by EPO in human EPO-responsive cells.