Objective: The influences of groin incision, duration of ischemia, and the effects of prostaglandin E1 (PGE1) on ischemia-reperfusion (I/R) injury of the hind limb in rabbits were evaluated. Design: A prospective study. Setting: Laboratory. Participants: In 64 rabbits, bilateral hind limb ischemia was induced by occlusion of the abdominal aorta. Volume changes, neuromuscular function of the hind limb, and creatine kinase (CK) release were measured as variables of tissue injury. Interventions: Eight rabbits served as untreated controls (CON). In 2 groups (each n = 14), 3 hours of ischemia were followed by 3 hours of reperfusion (I/R). In 2 different groups (each n = 14), 45 minutes of ischemia were followed by 2 hours of reperfusion. To determine effects of PGE1, 1 I/R group of each ischemia duration was treated intravenously with 80 ng/kg/min of PGE1 starting 30 minutes after the onset of ischemia (I/R-PGE1). To determine effects of groin incision on edema formation, volume changes were determined in the “operated” right (CON-R, 3h-R, 3h-PGE1-R and 45 min-R, 45 min-PGE1-R) or in the “nonoperated” left hind limb (CON-L, 3h-L, 3h-PGE1-L and 45 min-L, 45 min-PGE1-L), representing a subgroup analysis. Measurements and Main Results: Volume changes after I/R occurred only in operated legs after ischemia (3h-R: 2.3 ± 0.3 mL, p < 0.0001 v CON-R and 3h-L; 45min-R: 0.8 ± 0.2 mL, p < 0.01 v 45 min-L). PGE1 reduced edema formation in the operated legs (3h-PGE1-R: 1.0 ± 0.4 mL, p < 0.0001 v 3h-R; 45 min-PGE1-R: 0.5 ± 0.3 mL, p = 1.0 v 45 min-R). Groin incision without I/R had no effect on edema formation (CON-R: −0.13 ± 0.17 mL of baseline). The increase of CK release from 616 ± 584 U/L in controls to 5,921 ± 2,156 U/L after 3 hours of ischemia (p < 0.001) was attenuated by treatment with PGE1 (3,732 ± 2,653, p < 0.05 v I/R). Forty-five minutes of ischemia did not lead to cellular damage as measured by CK release (I/R: 606 ± 364 U/L). Recovery of neuromuscular function was not affected by PGE1. Conclusion: Development of edema during I/R depends on groin incision of the hind limb and on the duration of ischemia. The I/R injury is attenuated by PGE1 treatment, in terms of reduced edema formation and CK release, but not in terms of neuromuscular function.