To investigate the morphological changes of polymorphonuclar neutrophils (PMNs) induced by ONO-AE-248, a selective agonist of EP3.The morphological changes of PMNs treated with or without ONO-AE-248 were observed by electron microscope, fluorescence microscope and confocal microscope.A unique form of PMNs death was rapidly caused by ONO-AE-248. The agonist primarily induced morphological changes of PMN nucleus under electron microscope, including the fusion of the nuclear lobules same as a large round structure, decreasing of the compactness of chromatin, the blebbing and rupture of nuclear membrance. Observation of PMN nucleus under fluorescence microscope by DAPI staining gave the same conclusion. However, there were no apparent changes in other intracellular organelles. The structure and distribution of mitochondria of PMNs treated with ONO-AE-248 were different from the typical morphological changes of apoptotic PMNs. ONO-AE-248 exerted little effects on the exposure of cell membrane phosphatidylserine (PS).ONO-AE-248 can promote the non-apoptotic programmed cell death of PMNs in vitro. The events occurring in nucleus and mitochondria might be the early features of the novel cell death, which suggests that nucleus and mitochondria may be the reaction center of PMNs induced by ONO-AE-248.