In the last few years, three new heparin binding growth factors that interact with the Epidermal Growth Factor receptor (EGFR) and/or the related p185erbB-2 tyrosine kinase have been identified. Amphiregulin (AR) and Heparin-Binding EGF-like growth factor (HB-EGF) bind and activate the EGFR while Heregulin (HRG) acts through the p185erbB-2 and p180erbB-4 tyrosine kinases. Recently, activated macrophages were reported to secrete a p185erbB-2- and a heparin binding EGFR-stimulatory activities. We show here that activated monocytes secrete AR, HRG and HB-EGF-like molecules. Indeed, upon activation with Phorbol12, 13-dibutyrate (PDBu), the human monocytic-like THP-1 cells expressed high levels of AR, HRG and HB-EGF transcripts and released heparin binding factors that induced tyrosine phosphorylation of the EGFR in A431 cells and a protein of 185 kDa in MDA MB 453 cells. Similarly, activation of peripheral blood monocytes induces a dramatic increase of these three genes. Since EGFR, cerbB-2, c-erbB-4 transcripts are not or hardly detected upon activation, the occurrence of autocrine loops in these cells is unlikely. Therefore, secretion of these factors by activated monocytes may be implicated in the paracrine activation of the erb receptors thereby contributing to the epithelial and connective tissue proliferation.