Cardiopulmonary bypass (CPB) is associated with a systemic inflammatory response syndrome and disturbances in endothelial function of systemic arteries. FTY720, a non-selective agonist for sphingosine 1-phosphate (S1P) receptors, evokes lymphopenia by sequestration of lymphocytes from circulation to secondary lymphoid organs. SEW2871 is a selective agonist of S1P1 receptors. We investigated whether FTY720 and SEW2871 improve vascular reactivity after CPB in the rat. Experiments were done in male Wistar rats (n=48). Anesthesia-induction consisted of isoflurane (2.5–3%), followed by fentanyl and midazolam during CPB. After catheterization of the left femoral and carotid artery and the right heart, normothermic extracorporeal circulation was instituted for 60 min. Following 1 day of recovery, constriction to phenylephrine (PE) and serotonin (SE) and relaxation to acetylcholine of small mesenteric artery segments was assessed in a wired myograph system. Relaxation was expressed as % of preconstriction and analyzed as the area under the concentration-response curve (AUC, arbitrary units). Contractile responses were inhibited after both CPB and SHAM experimental procedures. In mesenteric artery, FTY720 normalized SE- and PE-mediated vascular reactivity after CPB. FTY720 also increased total relaxation to acetylcholine as compared with untreated CPB groups (AUC: 256.8±43.9 and 168.2± 28.4; respectively). SEW2871 produced vascular effects comparable with FTY720. FTY720 and SEW2871 improve vascular function in mesenteric after CPB. This pharmacological effect was mediated mainly through S1P1 receptors and did not require lymphopenia. S1P1 receptor agonism may provide a promising therapeutic intervention to prevent CPB-related vascular dysfunction.