Castleman's disease (CD) is characterized by lymph node enlargement due to hyperplasia of abnormal lymphoid follicles and paracortical lymphocytic hyaline vascular (HV) stroma or plasmacytosis (PC). The lymphoid follicles in CD show involuted germinal centers and prominent mantle zone lymphocytes. Ninety-seven cases clinically suspected to be CD were analyzed according to conventional histologic criteria established by Castleman and Keller for diagnosis. Twenty-two cases were excluded as nonspecific hyperplasia (12); Hodgkin's and non-Hodgkin's lymphoma (9); and multiple myeloma involving lymph node paracortex (1). The 75 remaining cases, consisting of 51 cases of CD and 24 with altered follicles or paracortex suggestive of CD, were further analyzed immunohistologically for changes in follicular dendritic reticulum cells (FDRC) using the monoclonal antibody Ki-M4p, for germinal center proliferation with Ki-S5, for mantle zone immunophenotype with Ki-B3 and Ki-B5, for paracortical plasmacytoid monocytes with Ki-M1p, and for plasma cell clonality by applying antibodies to kappa and lambda immunoglobulin light chains. Lymph nodes showing nonspecific follicular and paracortical hyperplasia were included as controls. Hyaline vascular CD and plasma cell CD showed enlarged, polyploid FDRC with prominent nucleoli, decreased germinal center proliferation, and mantle zone populations of immunophenotypically aberrant, Ki-B3-negative B lymphocytes. Thirty-seven percent of hyaline vascular CD and plasma cell CD contained plasmacytoid monocytes, and 15% showed interstitial areas of lambda predominant plasma cells. Plasmacytoid monocytes were common in hyaline vascular CD but rare in plasma cell CD. Cases suspected to be CD that demonstrated a mantle zone population of Ki-B3-negative B lymphocytes had clinical finding of POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal paraprotein, and skin changes or sclerotic bone lesions) syndrome and were reclassified as hyaline vascular CD, plasma cell CD, and mantle zone CD with an aberrant mantle zone immunophenotype only (lacking follicular center and paracortical histologic or immunohistologic abnormalities). Immunohistochemistry was valuable for identification of dysplastic FDRC, decreased germinal center proliferation, and plasmacytoid monocytes. In addition, immunohistochemistry was essential for detection of plasma cell clonality, an aberrant mantle zone immunophenotype, and mantle-zone-restricted CD that was devoid of diagnostic alterations of germinal center or paracortex.