High expression of CXCR5 is one of the defining hallmarks of T follicular helper cells (T FH), a CD4 Th cell subset that promotes germinal center reactions and the selection and affinity maturation of B cells. CXCR5 is also expressed on 20–25% of peripheral blood human central memory CD4 T cells (T CM), although the definitive function of these cells is not fully understood. The constitutive expression of CXCR5 on T FH cells and a fraction of circulating T CM suggests that CXCR5+ T CM may represent a specialized subset of memory-type T FH cells programmed for homing to follicles and providing B cell help. To verify this assumption, we analyzed this cell population and show its specialized function in supporting humoral immune responses. Compared with their CXCR5− T CM counterparts, CXCR5+ T CM expressed high levels of the chemokine CXCL13 and efficiently induced plasma cell differentiation and Ig secretion. We found that the distinct B cell helper qualities of CXCR5+ T CM were mainly due to high ICOS expression and pronounced responsiveness to ICOS ligand costimulation together with large IL-10 secretion. Furthermore, B cell helper attributes of CXCR5+ T CM were almost exclusively acquired on cognate interaction with B cells, but not with dendritic cells. This implies that a preferential recruitment of circulating CXCR5+ T CM to CXCL13-rich B cell follicles is required for the promotion of a quick and efficient protective secondary humoral immune response. Taken together, we propose that CXCR5+ T CM represent a distinct memory cell subset specialized in supporting Ab-mediated immune responses.