Human herpes virus-8 (HHV-8)-associated Castleman's disease (CD) is a rare non-cancerous B-cell lymphoproliferative disorder in human immunodeficiency virus (HIV)-positive patients. We report a case of HHV-8-associated CD in an HIV-positive patient with a previous history of Kaposi's sarcoma (KS). The patient presented with progressive splenomegaly and diffuse lymphadenopathy, which can be seen in multicentric CD, KS, and HIV-associated lymphoma. There are no reliable clinical or imaging features to differentiate these diseases. Lymph node biopsy confirmed HHV-8-associated CD and excluded KS and lymphoma. Due to differences in treatment options and prognosis between the three etiologies, it is important for radiologists to include HHV-8-associated CD in the differential diagnosis when encountering HIV-positive patients that present with diffuse lymphadenopathy.