High-fructose intake induces metabolic syndrome and cardiac dysfunction. Chronic intermittent hypobaric hypoxia (CIHH) preserves cardiac function during ischemia. We hypothesized that CIHH restores the impaired cardiac function in fructose-fed rats. Sprague-Dawley rats were randomly subject to treatment with fructose (10% fructose in drinking water for 6 weeks), CIHH (simulated 5000 m altitude, 6 h/day for 6 weeks in a hypobaric chamber), and CIHH plus fructose groups. In addition to an increase in blood pressure, fructose feeding caused elevated serum levels of glucose, fasting insulin and insulin C peptide, triglyceride, cholesterol, and mass ratio of heart to body. CIHH treatment decreased the arterial blood pressure, serum levels of biochemical markers, and cardiac hypertrophy in fructose-fed rats. Furthermore, CIHH treatment improved the recovery of left ventricular function after ischemia-reperfusion procedure (30 min global no-flow ischemia followed by 60 min of reperfusion) in rats with or without fructose feeding. In addition, CIHH treatment caused a significant increase in superoxide dismutase (SOD) activity and decrease in malondialdehyde level in cardiac myocardium experiencing ischemia-reperfusion in control and fructose-fed rats. Collectively, these data suggest that CIHH improve impaired cardiac function in fructose-fed rats through enhancing antioxidation in the myocardium.