The objective of the study was to evaluate the expression pattern of interleukin-6 (IL-6) to determine its utility in differentiating Castleman Disease subtypes and reactive lymphadenopathies. Paraffinembedded tissue blocks from 20 cases referred for assessment of Castleman Disease (CD) and 4 cases of reactive hyperplasia were selected for immunohistochemical staining with an IL-6 antibody. Six pathologists evaluated the hematoxylin and eosin stained tissue sections and IL-6 expression pattern. Of 20 CD referral cases, the pathologic diagnosis was CD in 14 cases and included 6 hyaline-vascular (HV-CD), 6 plasma cell (PC-CD) and 2 “mixed type”-CD cases. The remaining 6 referral cases showed morphologic features consistent with reactive lymphadenopathy. Patients with non-CD, reactive lymphadenopathies had clinical and/or laboratory features of systemic lupus erythematosus, Hashimoto's disease, viral infection or chronic cellulitis. The pattern of IL-6 expression differed between CD subtypes and non-CD cases. In PC-CD, IL-6 expression was detected in plasma cells and vascular endothelial cells; whereas IL-6 immunoreactivity was detected primarily in vascular endothelial cells in HV-CD. Interfollicular plasma cells were prominent in PC-CD and reactive lymphadenopathies; however, IL-6 expression was significantly increased in PC-CD compared to reactive lymph nodes. Together with morphologic features, the expression pattern of IL-6 detected by immunohistochemistry is helpful to distinguish CD subtypes and reactive mimics.