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To characterize the effect of the HIV-1 infection and antiretroviral treatment (ART) in the human memory B (MEB)-cell compartment.A cross-sectional study was designed to analyze MEB cells of HIV-1+ ART treated and ART-naive study participants, and uninfected individuals.Frequency and absolute counts of MEB cell subsets in blood were determined by multicolor flow cytometry. Spontaneous cell death and B-cell proliferative capacity was evaluated in vitro by cell culture and flow cytometry. Splenic function was determined by pitted erythrocytes quantification in HIV-1+ ART-treated study participants.HIV-1+ ART-treated individuals did not show functional hyposplenism despite the lack of recovery IgM+IgD+CD27+ marginal zone-like B cells. Moreover, two germinal center-dependent MEB cells subsets were also dysregulated in HIV-1+ individuals: IgM+IgD−CD27+ (IgM only) cells were increased, whereas the switched subset (IgM−IgD−) was reduced in viremic individuals. Althought ART restored the numbers of these populations; the switched MEB cells were enriched in CD27− cells, which showed the highest susceptibility to spontaneous cell death ex vivo. In addition, B cells from viremic individuals showed a poor response to B-cell receptor and toll-like receptor 9 stimulation that was circumvented when both stimuli were used simultaneously.B cells from HIV-1+ study participants show a poor stimulation capacity, that may be bypassed by the proper combination of stimuli, and a dysregulated MEB cell pool that suggest an affectation of the germinal center reaction, only partially normalized by ART. Interestingly, hyposplenism does not explain the lack of recovery of the marginal zone-like B cells in ART-treated HIV-1+ individuals.