Chronic intermittent hypoxia (CIH) results in systemic hypertension and altered vascular reactivity in human and rodents. We hypothesize that vascular smooth muscle (VSM) Na/Ca exchanger type-1 (NCX1) is a potential molecular mechanism mediating CIH-induced changes in vascular reactivity and blood pressure (BP). Wild type (WT) and transgenic (TG) mice with VSM-specific NCX1 overexpression were exposed to either CIH (1 min 5% nadir O2, followed by 1 min 21% O2; 8 hrs/day for 5 weeks), or normoxia (constant 21% O2). CIH resulted in greater BP elevation in TG (102 ± 3 mm Hg vs. 92 ± 6 mm Hg in normoxia, P < 0.05, n = 6 and 3, measured by intra-carotid artery catheterization under 1.5% isoflurane) than in WT (88 ± 4 mm Hg vs. 83 ± 2 mm Hg in normoxia, NS, n = 3 and 5) mice. Mesenteric small resistance arteries were then isolated and pressurized for diameter and wall thickness measurement. Compared to normoxia controls, CIH-exposed WT arteries exhibited increased resting myogenic tone (21 ± 2% vs. 16 ± 2% of PD in normoxia, P < 0.05, n = 5 each group). Moreover, myogenic reactivity in WT arteries of CIH-exposed mice shifted downward at lower range of intraluminal pressure (20-80 mm Hg), and upward at higher pressure (100-140 mm Hg). The effects of CIH were significantly greater in TG arteries compared to those in WT arteries, suggesting that VSM NCX1 augmented the myogenic response to CIH. Vasoconstrictions induced by phenylephrine (0.003-100 μM), greater in TG arteries, or high (60 mM) external K+ solution, were similar between control and CIH groups in the same genotype, suggesting that arterial contractility to agonist stimulation was not affected by CIH. Arterial wall thickness or passive diameters under various intraluminal pressures in Ca2+-free solution were not different between control and CIH groups in either genotype, suggesting a lack of arterial stiffness or remodeling. In summary, 1) CIH results in greater BP elevation in TG mice; 2) CIH leads to biphasic changes in myogenic reactivity in small resistance arteries; 3) Overexpression of VSM NCX1 exaggerates BP elevation in CIH, likely by modulating myogenic reactivity, suggesting that VSM NCX1 is a potential mechanism mediating CIH-induced hypertension.