We have previously shown that pentoxifylline (PTX) protects from vascular complications associated with insulin resistance (IR). Here, we investigated the protective effect of PTX against cardiac ischemia and dysfunction following experimental angina in IR. IR, along with its accompanying cardiac dysfunction, was induced in rats by a high-fructose (10% in drinking water) high-fat diet for 12 weeks. PTX was administered daily (30 mg⋅kg(-1)) during the last 4 weeks of the study. Experimental angina was induced by isoproterenol (10 µg⋅kg(-1)) administered by intravenous injection. Both before (baseline) and after the experimental angina, cardiac contractility was assessed by continuous recording in anesthetized rats via a microtip catheter inserted in the left ventricle, and cardiac conductivity was determined by a surface electrocardiograph. Serum glucose, insulin, tumor necrosis factor-α (TNFα), and adiponectin levels and lipid profile were also determined. Feeding the rats a high-fructose high-fat diet produced IR, as evidenced by significant hyperinsulinemia and hyperglycemia, and PTX administration did not affect this IR. When subjected to experimental angina, IR hearts were less resistant to the ischemia following induction of angina (reflected by the large ST height depression) compared with controls, and PTX completely prevented the excessive ST height depression in IR animals. In addition, left ventricular pressure development was largely attenuated during and after induction of angina in IR animals compared with controls. PTX administration prevented the excessive attenuation in ventricular pressure development in IR animals. IR was associated with elevated levels of the inflammatory cytokine TNFα, whereas PTX treatment elevated the serum level of the anti-inflammatory cytokine adiponectin. PTX alleviates cardiac ischemia and dysfunction following experimental angina in IR directly through inhibition of the low-grade inflammation that accompanies IR.