15-Deoxy-Δ 12, 14-PDJ 2 (15d-PGJ 2) is a degradation product of PGD 2 that has been proposed as an anti-inflammatory compound because of its various inhibitory effects, some of which are mediated by peroxisome proliferator-activated receptor-γ. In contrast to its reported inhibitory effects on macrophages and other cells, we found that this compound is a potent activator of eosinophils, inducing calcium mobilization, actin polymerization, and CD11b expression. It is selective for eosinophils, having little or no effect on neutrophils or monocytes. 15d-PGJ 2 has an EC 50 of∼ 10 nM, similar to that of its precursor, PGD 2. The concentrations of 15d-PGJ 2 required to activate eosinophils are thus much lower than those required for its anti-inflammatory effects (usually micromolar). 15-Deoxy-Δ 12, 14-prostaglandin D 2 (15d-PGD 2) is also a potent activator of eosinophils, with an EC 50 about the same as that of PGD 2, whereas Δ 12-PGJ 2 is slightly less potent. Eosinophils pretreated with PGD 2 no longer respond to 15d-PGJ 2, and vice versa, but in both cases the cells still respond to another eicosanoid proinflammatory mediator, 5-oxo-6, 8, 11, 14-eicosatetraenoic acid. This indicates that the effects of 15d-PGJ 2 are mediated by the DP 2/chemoattractant receptor-homologous molecule expressed on Th2 cells that has recently been identified in eosinophils. 15d-PGJ 2 is selective for the DP 2 receptor, in that it has no effect on DP 1 receptor-mediated adenylyl cyclase activity in platelets. We conclude that 15d-PGJ 2 and 15d-PGD 2 are selective DP 2 receptor agonists that activate human eosinophils with potencies at least 100 times greater than those for the proposed anti-inflammatory effects of 15d-PGJ 2 on other cells.