Patients with human immunodeficiency virus (HIV) infection are at increased risk for developing lymphoproliferative disorders. Multicentric Castleman's disease should always be kept in the differential diagnosis of HIV-positive patients suspected of having lymphoma to avoid misdiagnosis. We report the case of a 40-year-old HIV-positive homosexual man who presented with lower back pain and features highly suggestive of lymphoma including lymphadenopathy, elevated lactic dehydrogenase, and splenomegaly. The patient's plasma was positive by polymerase chain reaction for Kaposi sarcoma herpesvirus/human herpesvirus-8 (KSHV/ HHV8), and a lymph node biopsy revealed Multicentric Castleman's disease. He was started on highly active antiretroviral therapy, corticosteroids, valganciclovir, and rituximab. His back pain subsided, lymphadenopathy regressed, and he became KSHV/HHV8 negative. Albeit a rare condition, Castleman's disease should always be considered in immunocompromised patients suspected of having lymphoma.