The events responsible for cell injury after a tissue stimulation are only incompletely understood. The purpose of this study was to examine mechanisms of cell injury in two tissues, rat mesentery and cremaster muscle, after tissue stimulation withN-formylmethionyl-leucyl-phenylalanine (FMLP) and platelet-activating factor (PAF). The response was studied in the same animal in random order using normal and leukopenic rats. The tissues were exteriorized after pentobarbital anesthesia. Five to six vascularized areas were chosen in each tissue, and cell injury and hydroperoxide production were assessed visually by continuous superfusion with 1 μM propidium iodide and 5 μM dichlorofluorescin diacetate (DCFH), respectively. FMLP (1 × 10⁻⁸ M) and then PAF (1 × 10⁻⁸ M) were added to the superfusate, and measurements were made at several time points. The second tissue was then examined using the same protocol. In the cremaster, there was little hydroperoxide production, and the tissue injury was eliminated after leukopenia. Leukopenia had no effect on tissue injury in the mesentery. Although hydroperoxide production was observed, there was no correlation between it and the tissue injury. The level of preactivation showed no correlation with either tissue injury or hydroperoxide production. In light of these results, mast cell degranulation may be an important mechanism of tissue injury in the mesentery.