We previously showed that high sugar diets increase mortality and left ventricular dysfunction during pressure overload. The mechanisms behind these diet-induced alterations are unclear but may involve increased oxidative stress in the myocardium. The present study examined whether high fructose feeding increased myocardial oxidative damage and exacerbated systolic dysfunction following transverse aortic constriction (TAC) and if this effect could be attenuated by treatment with the antioxidant tempol. Immediately following surgery, TAC and sham mice were assigned to high starch (58% of total energy intake as cornstarch, 10% fat) or high fructose (61% fructose, 10% fat) diet with or without addition of tempol (0.1% w/w in the chow) and maintained on treatment for 8 weeks. In response to TAC, fructose-fed mice had greater cardiac hypertrophy (55.1% increase in heart weight to tibia length ratio) than starch-fed mice (22.3%). Treatment with tempol significantly attenuated cardiac hypertrophy in fructose-fed TAC mice (18.3% increase in heart weight to tibia). Similarly, fructose-fed TAC mice had a decreased left ventricular area of fractional shortening (from 38 ± 2% in sham to 22 ± 4% in TAC) which was prevented by treatment with tempol (33 ± 3%). Markers of lipid peroxidation in fructose-fed TAC hearts were also blunted by tempol. In conclusion, tempol significantly blunted markers of cardiac hypertrophy, LV remodeling, contractile dysfunction, and oxidative stress in fructose-fed TAC mice.