By linking surface Ig to the FcR Fc gamma RII on the mouse B lymphocyte surface, whole anti-Ig has been shown to block cell cycle entry and subsequent Ab production, a phenomenon called the "Fc receptor off-signal." IL-4 or blocking Ab to Fc gamma RII, present with whole anti-Ig, restores cell cycle progress to the levels observed with F(ab')2 anti-Ig. The current study demonstrates that under "off-signal" conditions with whole anti-Ig, the early entry of B cells into apoptosis was accelerated relative to medium alone or equimolar F(ab')2 anti-Ig. All reagents tested which opposed the whole-anti-Ig-induced blockade of B cell cycle entry also protected B cells from apoptosis (IL-4, PMA, dextran sulfate, and the monoclonal anti-Fc gamma RII 2.4G2). This protective effect was most evident at 4 to 12 h, waning at later times. Low dose cycloheximide partially protected B cells from whole anti-Ig-induced apoptosis, but acted as a survival factor, failing to advance B cells from G0 phase or stimulate thymidine incorporation. Additive early apoptosis-associated membrane changes were transiently seen when whole anti-Ig was combined with other apoptosis-accelerating agents (trifluoperazine, staurosporine, dexamethasone, ionomycin, high-dose cycloheximide), but hypodiploid nuclei did not show this effect. B cells from bcl-2 transgenic mice showed less apoptosis when cultured with whole anti-Ig, or with any of the other agents tested. At 4 h the bcl-2-associated reduction in hypodiploid nuclei was greater than the reduction in membrane unpacking, but by 16 h this difference was much less. These results suggest that acceleration of apoptosis contributes to the inhibition of proliferation induced by whole anti-Ig.