At present, whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines can elicit robust humoral and cellular immune responses in people living with HIV (PLWH) is still controversial. We assessed humoral and cellular immune response after the administration of the BNT162b2-mRNA-vaccine in seven antiretroviral therapy-treated PLWH patients and in nine HIV-negative health care workers (PWOH) over a 3-month span of time from the first vaccine dose. The neutralizing activity against both the European and the Delta variants declined after 3 months equally in both PLWH and PWOH. The gene expression analysis of factors involved in the antiviral immune response did not show any significant difference between PLWH and PWOH; among circulating cytokines/chemokines, a progressive decline was observed in the mean values of IL-1β, IL-5, IL-6, IL-13, and IL-15 in both PLWH and PWOH. Conversely, the ratio between naive and terminally differentiated T-CD4 effector memory showed a reduction trend over time in PLWH. Our findings showed no significant differences in the ability to mount an immune response after the administration of two SARS-CoV-2 mRNA BNT162b2 doses in PLWH and PWOH. However, as BNT162b2 vaccinated PLWH display an early waning immunity in the T cell compartment, the administration of a booster dose may be necessary to maintain a SARS-CoV-2-specific immune response.