Heart failure with reduced ejection fraction (HFrEF) is a common cause for admission within the Veterans Affairs (VA) Health Care System. It is associated with severe impairment of physical and mental health status, and carries a high 5-yr mortality rate of ~75%. Even though significant progress has been made in understanding its pathophysiology, currently, its management and treatment is based on therapeutic targeting of a limited number of receptors and pathways. Our team and others have made great progress in the last few years by understanding and harnessing the Transient Potential Receptor superfamily as regulators of cardiovascular function. Specifically, our laboratory has explored the role the vanilloid 2 (TRPV2) subtype plays in regulating calcium handling and contractility. This work has led us to understand that TRPV2 modulates contractility via increasing calcium cycling in myocytes on a beat-to-beat basis. We have used probenecid, a generic, globally available drug with an extremely safe profile that has been used for decades as a treatment for gout, as a TRPV2 agonist. Our work with this drug has demonstrated it to be a potent inotrope without apoptotic, chronotropic or arrhythmogenic effects in cardiomyocytes in vitro as well as in vivo murine and porcine models. These findings have been taken to the bedside with a recently published small phase 2 study of 20 adult patients with HFrEF (the ReProsper HF pilot study) where we demonstrated a mean improvement in left ventricular systolic and diastolic function with no adverse effects after only 1 week of treatment. The use of probenecid in HFrEF was also indirectly supported by a recent retrospective study of approximately 40,000 patients in the Medicare database that found treatment with probenecid (not specifically for heart disease) was associated with a 9% decreased risk of HF hospitalization. These studies strongly argue for the safety and potential efficacy of probenecid to improve systolic function and the need for a larger study, and of longer duration that also evaluates functional and health status outcomes in addition to systolic function. The overall objective of this study is the treatment of outpatient veterans with NYHA II-III heart failure with reduced ejection fraction (HFrEF) with probenecid to improve systolic and health function. Specifically, we are proposing a three-site double-blinded, randomized, placebo- controlled, three-site trial that will assess whether oral probenecid administered at 1 gr. orally twice per day for 180 days in patients with NYHA II-III HFrEF improves systolic function as measured via ejection fraction with echocardiography (aim 1); improves functional status as measured by exercise stress testing (aim 2); and improves self-report heart failure specific health status as measured by Kansas City Cardiomyopathy Questionnaire (KCCQ) and overall health status measured by EQ5D (aim 3). This trial is highly relevant to the VA population as HFrE...