IL-21 has a pro-apoptotic effect on freshly isolated B cells stimulated with LPS, and also induces Bcl6 expression in the activated B cells. However, a role for Bcl6 in the activated B cells is not known. When naive B cells from Bcl6-deficient mice were stimulated with LPS plus IL-21, those B cells died by apoptosis as wild-type B cells. Co-stimulation of those B cells with IL-4 partially rescued the wild-type B cells but not the Bcl6-deficient B cells from the IL-21-induced apoptosis. Bcl-2 was not up-regulated in both B cells stimulated with LPS plus IL-21 and IL-4. Bcl-X(L) and Bax were up-regulated in both B cells stimulated with LPS plus IL-4, and the co-stimulation with IL-21 did not modulate these up-regulations in wild-type B cells. However, the co-stimulation clearly suppressed the Bcl-X(L) up-regulation but not the Bax up-regulation in Bcl6-deficient B cells. Thus, Bcl6 is required for maintaining the Bcl-X(L) up-regulation in B cells stimulated with LPS plus IL-21 and IL-4, and the up-regulation may partially rescue the B cells from apoptosis induced by IL-21.