Although patients suffering from heart failure (HF) have an increased incidence of nonocclusive mesenteric ischemia after opened heart surgery, the impact of cardiopulmonary bypass with cardiac arrest (CPB) on mesenteric vascular circulation in such situation remains unexplored. Therefore, the present study investigates the effects of CPB on mesenteric vascular reactivity, regional metabolism, and oxidative stress in an experimental model of HF. Volume-overload HF was induced in six dogs by bilateral femoral arteriovenous fistula. Six sham-operated dogs were used as controls. Eight weeks later, the short-term effects of 90 min of CPB were assessed in vivo during acute experiments. The significant increase in left ventricular end-diastolic volume in HF animals did not influence the vasodilator response of the superior mesenteric artery to acetylcholine (ACH) and nitroprusside (SNP) under baseline conditions. However, reduced mesenteric oxygen delivery, increased oxygen extraction, and lactate release were found during CPB in the HF group. In addition, an increased free radical production was assessed in the HF group during (89 ± 23 x 106 relative light units [RLU]) and after CPB (93 ± 15 x 106 RLU) compared with controls (45 ± 15 and 49 ± 7 x 106 RLU, respectively). Finally, 90 min of CPB led to a more pronounced decrease of ACH- (−22% ± 5% vs. −42% ± 9%, P < 0.05) and SNP- (−14% ± 4% vs. −50% ± 7%, P < 0.002) induced mesenteric vasodilatations in the HF group compared with controls. We conclude that coexistent HF significantly enhances the pathological effects of CPB on the mesenteric vascular circulation by additionally altering endothelial and smooth muscle vascular function consequent to augmented oxidative stress.