Abstract: Prostaglandins of the E‐series stimulate B lymphocytes by enhancing immunoglobulin‐class switching and antibody production. Little is known about whether or not other prostaglandins affect B lineage cells and perhaps counterbalance the stimulatory effects of PGE₂. PGD₂ is a major product of cyclooxygenase in bone marrow and in macrophages, suggesting a role for this lipid product in immunological responses. PGD₂ undergoes dehydration to the biologically active prostaglandin 15‐deoxy‐Δ^12,14‐PGJ₂ (15d‐PGJ₂) that binds to the nuclear receptor known as peroxisome proliferator‐activated receptor gamma (PPAR‐γ). We found that normal mouse B cells and a Wvariety of B lymphoma cells (e.g., 70Z/3, WEHI‐231, CH12, and J558) express PPAR‐γmRNA and the 67‐kDa PPAR‐γ protein. 15d‐PGJ₂ had a dose‐dependent antiproliferative/cytotoxic effect on normal and malignant B cells, as shown by ³H‐thymidine and MTT assays. Only PPAR‐γ agonists (i.e., thiazolidinediones) mimicked the effect of 15d‐PGJ₂ on B lineage cells, indicating that the mechanism by which 15d‐PGJ₂ negatively affects B lineage cells involves PPAR‐γ. The mechanism whereby PPAR‐γ agonists induced cytotoxicity is via apoptosis, as shown by Annexin V assays. PPAR‐γ agonists may serve as a counterbalance to the stimulating effects of PGE₂, which promotes B‐cell differentiation. The use of prostaglandins, such as 15d‐PGJ₂, and synthetic PPAR‐γ agonists to induce apoptosis in B lineage cells may lead to the development of therapies for fatal PGE₂‐resistant B lymphomas.