Heart failure with preserved ejection fraction (HFpEF) is prevalent and often accompanied by the metabolic syndrome. Current treatment options are limited. Here we test the hypothesis that combined A1/A2B adenosine receptor blockade is beneficial in obese ZSF1 rats, an animal model of HFpEF with the metabolic syndrome. BG9928, a combined A1/A2B receptor antagonist, was administered orally (10 mg/kg/day) to obese ZSF1 rats (n=10) for 24 weeks (from 20 to 44 weeks-of-age). Untreated ZSF1 rats (n=9) served as controls. After 24 weeks of administration, BG9928 significantly lowered plasma triglycerides (mg/dL: Control Group, 4351 ± 550; BG9928 Group, 2900 ± 551) without adversely affecting plasma cholesterol or activating renin release. BG9928 significantly decreased 24-hour urinary glucose excretion (mg/kg/day: Control Group, 823 ± 179; BG9928 Group, 196 ± 80) and improved oral glucose tolerance, polydipsia, and polyuria. BG9928 significantly augmented left ventricular diastolic function in association with a reduction in cardiac vasculitis and cardiac necrosis. BG9928 significantly reduced 24-hour urinary protein excretion (mg/kg/day: Control Group, 1702 ± 263; BG9928 Group, 1076 ± 238), and this was associated with a reduction in focal segmental glomerulosclerosis, tubular atrophy, tubular dilation, and deposition of proteinaceous material in the tubules. These findings show that in a model of HFpEF with the metabolic syndrome, A1/A2B receptor inhibition improves hyperlipidemia, exerts antidiabetic actions, reduces HFpEF, improves cardiac histopathology, and affords renal protection. We conclude that chronic administration of combined A1/A2B receptor antagonists could be beneficial in patients with HFpEF, particularly those with comorbidities such as obesity, diabetes, and dyslipidemias