This study investigated whether idoxifene, a selective estrogen receptor modulator (SERM), exerted protective effects against ischemia-reperfusion-induced shock. Ovariectomized rats were treated with vehicle, idoxifene, or 17-estradiol for 4 days. Rats were subjected to splanchnic artery occlusion (SAO) followed by reperfusion (SOA/R). In vehicle-treated rats, SAO/R resulted in hypotension, hemoconcentration, increased plasma tumor necrosis factor (TNF)- levels, intestinal neutrophil accumulation, and endothelial dysfunction. 17-Estradiol treatment increased plasma estradiol concentration and reduced SAO/R-induced tissue injury. Idoxifene treatment had no effect on plasma estradiol concentration but reduced SAO/R-induced hemoconcentration (+8.8 ± 1.3 vs. +14 ± 1.3% in the vehicle group, P < 0.01), TNF- production (98 ± 3.2 vs. 214 ± 13 pg/ml, P < 0.01), and neutrophil accumulation (0.025 ± 0.005 vs. 0.047 ± 0.005 U/g protein, P < 0.01). It also improved endothelial function, prolonged survival time (172 ± 3.5 vs. 147 ± 8 min, P < 0.01), and increased survival rate (69 vs. 23%, P < 0.01). Moreover, treatment with 17-estradiol or idoxifene in vivo reduced TNF--induced endothelial dysfunction in vitro. Taken together, these results demonstrated that idoxifene exerted estrogen-like, endothelial-protective, and antishock effects in ovariectomized rats, suggesting that SERMs have therapeutic potential in tissue injury resulting from ischemia-reperfusion.