Apoptosis constitutes the primary mechanism by which noncycling plasma cells are eliminated after the secretion of Ag-specific Abs in a humoral immune response. The underlying mechanism is not known. Here, we demonstrate that the expression of both TRAIL/Apo-2 ligand and the death receptors (DR) DR5 and DR4, but not Fas, are sustained in IL-6-differentiated Ig-secreting human plasma cells as well as primary mouse plasma cells generated in a T-dependent immune response. Plasma cell apoptosis is induced by both endogenous and exogenous TRAIL ex vivo, suggesting that TRAIL-mediated killing may, in part, be plasma cell autonomous. By contrast, resting and activated B cells are resistant to TRAIL killing despite comparable expression of TRAIL and DRs. The preferential killing of plasma cells by TRAIL correlates with decreased expression of CD40 and inactivation of NF-κB. These results provide the first evidence that primary plasma cells synthesize TRAIL and are direct targets of TRAIL-mediated apoptosis, which may relate to the inactivation of the NF-κB survival pathway.