Abstract Peroxisome proliferator-activated receptor γ (PPARγ) is a transcription factor important in fat metabolism and is emerging as an important regulator of immunity and inflammation. We previously demonstrated that normal and malignant B lineage cells express PPARγ and die by apoptosis after PPARγ agonist exposure. In this study, we used the WEHI-231 mouse B lymphoma and normal mouse spleen B lymphocytes to elucidate the mechanism of PPARγ agonist-induced apoptosis, and to determine whether an apoptosis rescue mechanism exists. In WEHI-231 cells, the natural PPARγ agonist 15-deoxy-Δ12,14-PGJ2 and the synthetic PPARγ agonist ciglitazone induced activation of caspase 3 and caspase 9, a decrease in mitochondrial membrane potential, and caused cleavage of the caspase substrate poly(ADP-ribose) polymerase. We next tested whether CD40, whose engagement delivers a potent prosurvival signal for B cells, could protect B cells from PPARγ agonist-induced apoptosis. CD40 engagement with CD40L significantly blunted the ability of PPARγ agonists to induce apoptosis of B lymphocytes and prevented the inhibition of NF-κB mobilization by 15-deoxy-Δ12,14-PGJ2 and ciglitazone. Interestingly, PPARγ agonists induced an increase in IκBα and IκBβ protein levels, which was prevented with CD40 engagement. The rescue mechanism induced by CD40 engagement was dependent on NF-κB, as an NF-κB inhibitor prevented rescue. Apoptosis induction by PPARγ ligands may be important for immune regulation by killing B lymphocytes as a rapid means to dampen inflammation. Moreover, the ability of PPARγ agonists to kill malignant B lineage cells has implications for their use as anti-B lymphoma agents.