Abstract Purpose: The aim of this study was to investigate the biological and clinical significance of epidermal growth factor receptor (EGFR) signaling pathway in follicular dendritic cell sarcoma (FDC-S). Experimental Design: Expression of EGFR and cognate ligands as well as activation of EGFR signaling components was assessed in clinical samples and in a primary FDC-S short-term culture (referred as FDC-AM09). Biological effects of the EGFR antagonists cetuximab and panitumumab and the MEK inhibitor UO126 on FDC-S cells were determined in vitro on FDC-AM09. Direct sequencing of KRAS, BRAF, and PI3KCA was conducted on tumor DNA. Results: We found a strong EGFR expression on dysplastic and neoplastic FDCs. On FDC-AM09, we could show that engagement of surface EGFR by cognate ligands drives the survival and proliferation of FDC-S cells, by signaling to the nucleus mainly via MAPK and STAT pathways. Among EGFR ligands, heparin-binding EGF-like growth factor, TGF-α and Betacellulin (BTC) are produced in the tumor microenvironment of FDC-S at RNA level. By extending this finding at protein level we found that BTC is abundantly produced by FDC-S cells and surrounding stromal cells. Finally, direct sequencing of tumor-derived genomic DNA showed that mutations in KRAS, NRAS, BRAF, and PI3KCA, which predicts resistance to anti-EGFR MoAb in other cancer models, are not observed in FDC-S. Conclusion: Activation of EGFR by cognate ligands produced in the tumor microenvironment sustain viability and proliferation of FDC-S indicating that the receptor blockade might be clinically relevant in this neoplasm. Clin Cancer Res; 19(18); 5027–38. ©2013 AACR.