In the present study, the anti-inflammatory action of lysophosphatidylethanolamine (lysoPtdEtn), orally administered, in zymosan A-induced peritonitis was examined. Oral administration of 2-DHA-lysoPtdEtn (ED(50), ~111 μg/kg) or 2-ARA-lysoPtdEtn (ED(50), 221 μg/kg) was found to inhibit the plasma leakage in mice treated with zymosan A. In support of this, 2-polyunsaturated acyl-lysoPtdEtn diminished the formation of LTC(4), a lipid mediator responsible for vascular permeability. Next, 2-DHA-lysoPtdEtn (ED(50), 110 μg/kg) or 2-ARA-lysoPtdEtn (ED(50), 123 μg/kg) effectively inhibited the leukocyte extravasation into the peritoneum. Consistent with this, each polyunsaturated-lysoPtdEtn diminished the formation of LTB(4) and 12-HETE, potent chemotactic factors. Additionally, the level of pro-inflammatory mediator (IL-1 β, IL-6, TNF-α or NO) was lowered remarkably in contrast to the augmentation of anti-inflammatory interleukin IL-10. Furthermore, 2-(15-HETE)-lysoPtdEtn and 2-(17-HDHE)-lysoPtdEtn, 15-lipoxygenation product of 2-ARA-lysoPtdEtn and 2-DHA-lysoPtdEtn, respectively, were more potent than corresponding lysoPtdEtn, suggesting the action of 2-acyl-lysoPtdEtn might be expressed through 15-lipoxygenation. In support of this, the formation of 15-HETE and LXA(4) was upgraded in accordance with an increasing dose of 2-ARA-lysoPtdEtn. Separately, anti-inflammatory actions, 2-polyunsaturated acyl-lysoPtdEtns also drastically diminished leukocyte infiltration in a later phase of zymosan A-induced peritonitis, indicating that these lipids also possess pro-resolving activity. Taken together, it is suggested that polyunsaturated lysoPtdEtns and their lipoxygenation derivatives, could be classified as potent anti-inflammatory lipids.