Multicentric Castleman disease (MCD) is a devastating human herpesvirus 8 (HHV-8)–related lymphoproliferative disorder that occurs in immunocompromised persons. To determine the role of immune responses in MCD, we studied the frequency, antigenic repertoire, differentiation, and functional profile of HHV-8–specific CD8⁺ T cells in MCD patients and in human immunodeficiency virus–coinfected asymptomatic HHV-8 carriers (AC). Screening CD8⁺ T-cell responses with ELISpot interferon-γ (IFN-γ) assays using 56 peptides on 6 latent and lytic HHV-8 proteins showed that MCD and AC patients had responses of similar magnitude and antigenic repertoire and identified a new 10-mer human leukocyte antigen B7 CD8 epitope in K15. Intracellular IFN-γ staining showed significantly more CD45RA⁻CCR7⁻CD27⁻ CD8⁺IFN-γ⁺ cells (late phenotype) and significantly fewer CCR7⁻CD27⁺CD45RA⁻ cells (early and intermediate phenotype) in MCD than in AC patients. This phenotypic shift was not found for Epstein-Barr virus–specific CD8⁺ T cells tested as controls. HHV-8 viral loads were negatively correlated with early and intermediate effector memory cells. HHV-8–specific T cells were polyfunctional (secretion of IFN-γ, tumor necrosis factor-α, macrophage inflammatory protein-1β, and/or CD107a) in both MCD and AC patients. In conclusion, MCD is not associated with a lack of HHV-8–specific CD8⁺ T cells or limitation of their functional profile. Their differentiation increases with HHV-8 viral load. These results offer new insight into the pathophysiology of MCD.