Reperfusion injury by the abrupt restoration of circulation after the prolonged ischemia has been remained unsolved problem in the reconstructive microsurgery. We tested the hypothesis that a procedure of intermittent interruption of reperfusion, i.e., postconditioning (post-con) attenuates ischemia/reperfusion (I/R) injury of rat epigastric skin flap. A complete 4 hours of ischemia was generated by occlusion of the pedicle of dissected flap. The post-con procedure was started at the end of ischemia. A cycle of 15 seconds of full reperfusion, followed by 15 seconds of complete reocclusion was repeated six times (3 min of total intervention) prior to the unlimited reperfusion. Flap necrosis area of post-con group was compared with sham (no ischemic exposure) and control (4 hours of ischemia followed by full reperfusion without intervention) groups at postreperfusion day 5. Histology and MPO activities of flaps were evaluated. The post-con group showed significantly reduced flap necrosis at the end of 5 days of reperfusion compared with the control. Decreased inflammatory cell infiltration and MPO activity indicated post-con attenuated acute inflammatory reaction caused by I/R. This study reports for the first time that ischemic post-con effectively attenuates skin flap I/R injury. With further study, post-con may eventually be clinically applicable for the I/R injury as an “after-injury strategy.” © 2008 Wiley-Liss, Inc. Microsurgery, 2008.