We previously showed that pretreatment with a solution of ethyl pyruvate in a calcium-containing balanced salt solution, Ringer's ethyl pyruvate solution (REPS), ameliorates gut mucosal damage in rats subjected to mesenteric ischemia/reperfusion. Herein, we sought to test the hypothesis that REPS would be beneficial as a post-treatment (i.e., resuscitation fluid) for hemorrhagic shock. Anesthetized Sprague-Dawley rats were bled to a mean arterial pressure (MAP) of 40 mmHg until 40% of shed blood was returned. The animals then were resuscitated over 60 min with the remaining shed blood plus twice the shed blood volume as either Ringer's lactate solution (RLS) or REPS. In Experiment 1, RLS or REPS was then infused for 3 h more (or until death) at 3 mL/kg/h. Read-outs were post-resuscitation ileal mucosal permeability to fluorescein-labeled Dextran with an average molecular mass of 4000 Da (FD4) and survival. Permeability, determined just before death (MAP < 40 mmHg) or after 4 h of resuscitation, was assessed using an ex vivo everted gut sac technique and is expressed as a clearance (nL/cm/min). In Experiment 2, the read-outs were ileal FD4 permeability measured at 60 min after starting resuscitation and gut and liver malondialdehyde (MDA) formation. FD4 clearance data were logarithmically transformed prior to performing statistical analyses. In Experiment 1, 4/8 (50%) of RLS-treated rats survived 4 h after resuscitation whereas 7/7 (100%) of REPS-treated rats survived (P< 0.05). Ileal FD4 clearances were 105 +/- 30*, 85 +/- 34*, and 38 +/- 7 for all rats treated with RLS, surviving rats treated with RLS, and rats treated with REPS, respectively (the asterisk indicates P < 0.05 vs. REPS). In Experiment 2, ileal FD4 clearances were 71 +/- 13* and 34 +/- 8 for rats treated with RLS and REPS (n = 5 each), respectively. Post-resuscitation levels of MDA in the ileum and liver were significantly lower in rats treated with REPS as compared with RLS. Resuscitation with REPS, a stable and nontoxic antioxidant solution, improves survival and ameliorates ileal mucosal permeability in a rat model of severe hemorrhagic shock.