Naive CD8+ T cells differentiate into distinct cytokine-secreting subsets: T helper (Th)1-like cytotoxic T cells (Tc1) and Th2-like Tc2. Although Th2 cells provide strong B cell help, we show that Tc2 cells secreting the same cytokines provide only modest B cell help for IgM production, and only when large numbers of B cells were stimulated with small numbers of Tc2 cells. Lack of effective B cell help by Tc2 cells was attributable partly to their cytotoxicity towards B cells. Both Tc1 and Tc2 cells killed small resting B cells mainly by a perforin-dependent mechanism. In contrast to normal Tc2 cells, perforin-deficient Tc2 cells failed to kill small resting B cells and induced IgM and IgG1 production, although their B cell help was significantly lower than that mediated by Th2 cells. This may be partly attributable to the ability of Tc2 but not Th2 cells to kill activated B cells even in the absence of perforin. Plate-bound anti-CD3 antibodies inhibited Tc2 killing of B cells and induced substantial immunoglobulin production. Additionally, Tc1 and Tc2 cells failed to express CD40 ligand (CD40L), whereas Th1 and Th2 cells expressed high levels of CD40L. Stimulation of Tc1 and Tc2 cells with plate-bound anti-CD3 antibodies for extended periods resulted in low-level expression of CD40L. Proliferation of small resting B cells correlated with immunoglobulin production: proliferation was promoted strongly by Th1 and Th2, weakly by normal Tc1 and Tc2, and moderately by perforin-deficient Tc1 and Tc2 cells. Thus, Tc2 cells may not contribute significantly to cognate B cell help during normal responses.