The present study shows that tetanus toxoid (tet) booster releases to the human circulation 2 subsets of specific plasma cells (PCs), as defined by phenotype and morphology, which clearly differed in the staining capacity of their cytoplasmic antibodies (Abs) with fluorescein isothiocyanate (FITC)–labeled tet–fragment C (tetC). These cells, called tetC^HIGH and tetC^INT PCs according to their either high or intermediate FITC-tetC staining capacity, exhibit similar rapid temporary kinetics in the blood (5-8 days after boost), contain many cycling cells, express equivalent amounts of BLIMP-1 mRNA, and produce similar quantities of IgG. However, Abs synthesized by tetC^HIGH PCs show a tetC affinity more than 10 times higher than that exhibited by tetC^INT PC Abs, and indicated by IGVH sequence analysis. Chemotaxis to CXCL12, a requisite for bone marrow (BM) PC homing, is similar for both cell types. Circulating nonspecific and tetC^INT PCs, but not tetC^HIGH PCs, tend to undergo spontaneous apoptosis, as demonstrated by APO2.7 and activated caspase-3 expression, and cell recovery. These results indicate that tet booster generates 2 discrete subsets of specific PCs exhibiting different ranges of Ab affinity for the immunogen, and that only those synthesizing high-affinity Abs show enhanced survival. This inherent property may be essential for determining the BM fate of PCs secreting high-affinity Ab.