Inflammation has been suggested to be associated with stress-induced depression and cardiovascular dysfunction. Tumor necrosis factor alpha (TNF-alpha) is a major cytokine in the activation of neuroendocrine, immune, and behavioral responses. In this study, we investigated the effects of infliximab (a TNF-alpha inhibitor) on endothelium-dependent vascular reactivity, systemic blood pressure, and endothelial nitric oxide synthase (eNOS) immunoreactivity in the unpredictable chronic mild stress (UCMS) model of depression in rats. There was no significant change between all groups in the systemic blood pressure. In UCMS, endothelium-dependent relaxation of the smooth muscle in response to carbachol was significantly decreased with 50 % maximal response (E (max)) and pD2 values compared with the controls. Infliximab was able to reverse this UCMS effect. Relaxation in response to the nitric oxide (NO) donor sodium nitroprusside and papaverine and KCl-induced contractile responses was similar between groups. In UCMS, decreased expression of eNOS was detected. Moreover, there was no significant change in UCMS + infliximab group with respect to control rats. Our results suggest that tumor necrosis factor-alpha (TNF-alpha) could be a major mediator of vascular dysfunction associated with UCMS, leading to decreased expression of eNOS.