The factors regulating the growth of follicular dendritic cell (FDC) sarcoma are currently unknown. Using cDNA microarray analysis, we found that the epidermal growth factor receptor (EGFR) is expressed in FDC sarcoma. We immunohistochemically examined the expression of EGFR in a larger series of FDC sarcomas and in nonneoplastic FDCs. This included 8 cases of FDC sarcoma, 12 cases of hyaline vascular Castleman's disease (CD), 5 cases of human herpesvirus 8 (HHV8)-positive plasma cell CD, 7 cases of HHV8-negative plasma cell CD, 13 cases of reactive lymph nodes, 3 cases of reactive tonsils, 10 cases of follicular lymphoma, 6 cases of nodular mantle cell lymphoma, and 6 cases of angioimmunoblastic T-cell lymphoma. EGFR was expressed in tumor cells in 7 of 8 cases (88%) of FDC sarcoma (strongly in 4 cases and moderately in 3 cases). The single EGFR-negative case had an anaplastic appearance and a more aggressive clinical behavior. EGFR was also expressed by FDC in all types of CD (strongly in 4 cases, moderately in 16 cases, and weakly in 4 cases). Immunostaining results were negative or only weakly positive for EGFR in FDC of reactive lymph nodes and tonsils, and in the FDC networks of follicular lymphoma, mantle cell lymphoma, and angioimmunoblastic lymphoma. The up-regulation of EGFR in FDC of CD was paralleled by an increase in EGFR expression in the surrounding perifollicular fibroblastic reticulum cells suggesting coordinate regulation. These findings identify a differentially expressed growth regulatory receptor common to both FDC sarcoma and CD, identifying a target for possible therapy in unresectable or refractory cases.