OBJECTIVE Pentoxifylline lessens the metabolic derangements associated with ischemia-reperfusion injury. This study evaluated the effects of pentoxifylline on platelet-activating factor (PAF) production and tissue injury during skeletal muscle ischemia-reperfusion injury. METHODS The isolated canine gracilis muscle model was used. Group 1 muscles were subjected to 5 hours of ischemia and 20 hours of reperfusion (n = 10); group 2 muscles received pentoxifylline, 15 mg/kg, systemic infusion 10 minutes before reperfusion (n = 6); group 3 muscles received pentoxifylline, 25 mg/kg, systemic infusion 10 minutes before reperfusion (n = 6). PAF was measured from muscle venous effluent by the scintillation proximity assay method. Muscle injury was assessed by vital staining and planimetry. RESULTS PAF levels in group 2 were decreased at 10, 15, and 30 minutes of reperfusion compared with group 1 but did not reach significance. PAF levels in group 3 were decreased at all times of reperfusion compared with group 1 but attained significance only at 10 minutes of reperfusion (p < 0.05). No significant differences in muscle weight were noted among the three groups. No differences in the extent of muscle necrosis was observed between group 1 (77.26% +/- 20.38%) and group 2 (60.49% +/- 23.97%) (p = 0.08); there was a significant reduction in the extent of muscle necrosis in group 3 (44.55% +/- 21.47%) compared with group 1 (p < 0.05). CONCLUSIONS The administration of pentoxifylline at 25 mg/kg before reperfusion of ischemic skeletal muscle decreased significantly the extent of muscle necrosis and PAF levels in the venous effluents at all times of reperfusion (significantly at 10 minutes). These results suggest that pentoxifylline may decrease tissue injury of ischemia-reperfusion by inhibiting the production of PAF during critical periods of reperfusion.