The monoclonal antibody D2-40 recognizes the membrane protein podoplanin, which is an established marker for germ cell tumors, mesotheliomas, and other tumor types and is also expressed in a variety of normal cells including follicular dendritic cells (FDCs). To determine whether podoplanin represents an effective FDC marker for pathologic lymph nodes, we compared immunohistochemical studies (sensitivity, staining patterns, and intensity of staining) for podoplanin (D2-40) with those of the traditional FDC markers CD21, CD35, and clusterin. Paraffin sections of 26 lymph nodes were analyzed, including 4 cases of nodular lymphocyte-predominant Hodgkin lymphoma, 4 angioimmunoblastic T-cell lymphoma, 8 follicular lymphoma (including 3 cases with a component of diffuse large B-cell lymphoma), 5 hyaline-vascular Castleman disease, and 5 reactive lymph nodes with follicular hyperplasia. In all cases, qualitatively and quantitatively podoplanin represented a highly effective marker for detection of FDCs, with staining intensity equal to or greater than that observed for other FDC markers. This study demonstrates that podoplanin is an excellent marker for FDCs and adds to its growing list of diagnostic applications.