Recent studies document the importance of endothelial dysfunction (ED) in cancer development and metastasis. We previously reported that vascular oxidative stress and inflammation result in ED in animals bearing brain murine metastatic breast carcinoma (BCa). Substance P (SP)， a neuropeptide found in sensory nerve terminals， was reported to enhance anti-tumoral effects of conventional treatments. SP was also reported to have anti-oxidative effects. We therefore examined the effects of continuous exposure to low dose SP on vascular ED observed in metastatic BCa. In this study， cells derived from brain metastasis of 4T1 murine BCa (denoted as 4TBM) were used. Female Balb-c mice 8-10 weeks old were divided into following groups: Control (Hanks' balanced salt solution injected)， injected with 4TBM orthotopically， injected with 4TBM orthotopically and then treated with SP via an osmotic mini-pumps (0.1 mM， pumping rate 0.11 μl/hr). Thoracic aorta was removed 20-26 days after injection of tumor cells. Isometric tension studies were performed in response to potassium chloride， phenylephrine， acetylcholine (an endothelium-dependent vasodilator)， and sodium nitroprusside (an endothelium-independent vasodilator). On one hand， presence of tumor resulted in significant inhibition of vascular response to ACh in untreated mice. On the other， in vivo SP treatment restored the diminished relaxation response to ACh in thoracic aorta rings obtained from metastatic BCa bearing mice. These findings suggest that SP can inhibit tumor-induced ED which might be partly responsible from reported anti-tumoral effects of SP. Furthermore， protective effects of SP on vascular endothelium may prevent cardiovascular diseases in cancer patients.