A monoclonal antibody to CD72, the 45‐kDa human homolog of marine Lyb‐2, was found to augment selective activation pathways in tonsillar B lymphocytes. By itself, CD72 antibody provided a weak direct stimulus to resting B cells as assessed by [³H]dThd incorporation; this was modestly enhanced on the addition of interleukin 4 (IL 4) or following ligation of surface CD40. CD72‐delivered signals were more evident in co‐stimulation assays with phorbol ester and with a synergistic combination of IL 4 and CD40 antibody, but not with calcium ionophore or a CD23 antibody; rapidly cycling B cells were refractory to signaling via CD72 whether or not other co‐stimuli were present. A unique feature of the CD72‐delivered signal was its ability to enhance synergistically stimulations triggered with immobilized antibody to IgM, while failing to augment responses initiated by soluble anti‐μ. On direct culture of resting B lymphocytes with CD72 antibody, an approximately twofold increase in the expression of major histocompatibility complex class II DQ antigen was observed, an augmentation similar to that achieved with IL 4; CD72 antibody also mimicked IL 4 in its ability to drive G₀ cells into the early G₁ phase of cell cycle. In contrast to IL 4‐promoted stimulation, CD72 antibody failed to up‐regulate the surface expression of either IgM or the CD23 antigen. CD72 expression itself was found to be weak on resting B lymphocytes and was modestly enhanced following culture with IL 4. The findings are discussed with reference to observations made on the triggering of murine B lymphocytes through Lyb‐2 and within the context of previously defined human B cell activation pathways.