ABSTRACT In the global response to the current mpox epidemic, understanding immune memory to the vaccinia virus and cross‐immunity to the mpox virus (MPXV) among people living with HIV (PLWH) is critical. Blood samples were collected from PLWH born between 1949 and 2002 without MPXV infection, as well as from sex‐ and age‐matched healthy donors (HD). Note that 62% and 56% of vaccinated PLWH born before 1980 had antibodies against the vaccinia virus Tiantan (VTT) strain and MPXV, respectively, though these seropositivity rates were lower than in HD (84% vs. 80%). Neutralizing antibodies were detected in 9% of PLWH, compared to 32% in HD. Notably, in PLWH with CD4 T‐cell counts below 500 cells/mm 3 , VTT‐IgG and MPXV‐IgG titers, as well as VTT‐specific memory B cells, were significantly reduced. In PLWH with CD4 T‐cell counts below 350 cells/mm 3 , CD4 + memory T‐cell responses were diminished, particularly in IFN‐γ and TNF‐α responses. In contrast, CD8 + T‐cell responses to MPXV were comparable in PLWH regardless of CD4 T‐cell counts. These findings highlight the diminished humoral and CD4 + T‐cell responses in PLWH, particularly in those with lower CD4 T‐cell counts, and underscore the necessity for targeted vaccination strategies in this population.