Abstract: Obstructive sleep apnea (OSA) causes intermittent hypoxia (IH) associated with hypertension, insulin resistance and a systemic inflammatory response. We evaluated the effects of melatonin on vasodilation, capillary perfusion in hamster cheek pouch and insulin resistance, hypertension, and reactive oxygen species (ROS) and nitrate/nitrite levels after IH for 4 wk. Syrian hamsters were divided into four groups: control group (CON), IH group, and melatonin (10 mg/kg) intraperitoneally administered daily for 4 wk/30 min before intermittent air (MEL) or IH (IH + MEL) exposure. IH alone caused elevated blood pressure, increased hematocrit, fasting hyperglycemia, elevated ROS and nitrite/nitrate levels, and vasoconstriction and reduced microvascular perfusion. Melatonin treatment of IH-exposed animals decreased blood pressure, blood glucose, and ROS and nitrite/nitrate levels, and increased vasodilation and capillary perfusion. An oral glucose tolerance test was performed after 4 wk of IH. During the last 30 min of the hyperinsulinemic euglycemic clamp, blood glucose, and insulin levels were identically matched between groups, but the glucose infusion rate was significantly reduced in IH (29.9 ± 1.9 mg/kg/min) versus IH + MEL group (45.4 ± 1.5 mg/kg/min, P < 0.05) demonstrating a decrease in insulin sensitivity. These results suggest that ROS and nitrite/nitrate levels play important roles in the microvascular dysfunction in IH and that this process is attenuated by melatonin. In conclusion, protection induced by melatonin against functional and metabolic impairment in IH is related to the regulation of ROS and nitrite/nitrate levels in the microcirculation. These observations may have importance to OSA pathological changes.