Intestinal ischemia-reperfusion (I/R) provokes polymorphonuclear neutrophil (PMN)-mediated lung injury via a process characterized by circulating PMN priming, pulmonary PMN sequestration, and increased microvascular leak in the lung. We found in rats subjected to intestinal I/R (ischemia 45 min and reperfusion 6 h) that 1) intestinal phospholipase A2 (PLA2) was activated during ischemia, 2) circulating PMN priming (assessed by superoxide production with N-formyl-Met-Leu-Phe) occurred after 1 h reperfusion, and 3) exaggerated 125I-labeled albumin lung leak occurred after 2 h reperfusion, compared with sham-treated animals (P < 0.05). Treatment with a PLA2 inhibitor, quinacrine, within 15 min of reperfusion reversed the exaggerated gut PLA2 activity and abrogated subsequent PMN priming and lung leak (P < 0.05). However, when quinacrine was administered after 2 h of reperfusion, circulating PMN priming and lung leak continued to evolve despite suppression of intestinal PLA2 activity. We conclude that intestinal PLA2 activation may be a prerequisite for the sequelae of circulating PMN priming and pulmonary microvascular leak observed after intestinal I/R.