Hearts of NaCl-induced hypertensive-glucose intolerant (HGI) rats develop reduced infarcts after ischemia-reperfusion injury (IRI) than their hypertensive (H) counterparts. Because high intake of saturated fat is a major risk factor for ischemic heart disease, we tested the hypothesis that chronic (18 weeks) consumption of a high saturated fat diet increases susceptibility to IRI, an effect more marked in the HGI rats than in the H rats. The fat-fed H (HFAT) rat displayed significantly higher body weight and plasma leptin content compared to the H, HGI, or fat-fed HGI (HGIFAT) rats which all showed similar values. In contrast, plasma triglyceride concentration was significantly higher in the HGIFAT rat than in the other three groups. Plasma insulin concentration was similar in the two H groups but higher than that of the two HGI groups. Compared to the H rat, the HGI rat was markedly glucose intolerant, with fat feeding causing comparable worsening of glucose intolerance in each group. The HGIFAT rats displayed a reduction in baseline myocardial contractility and relaxation and a higher end-diastolic pressure compared to the other three groups. Infarct size was significantly lower in the HGI rats than in the H rats. Although fat feeding did not affect infarct size of the H rat, it worsened that of the HGIFAT rat thereby abrogating the differential that existed between the H and HGI rats. In conclusion, excess fat feeding impairs myocardial function of HGI rats and increases their susceptibility to IRI. These findings are of relevance to the metabolic syndrome that manifests as a cluster of insulin resistance, dyslipidemia, and systemic hypertension.