Background Risk factors of heart failure with preserved ejection fraction (HFpEF) share those of arteriosclerosis. Arteriosclerosis stiffens arterial wall, thereby impairs baroreceptor transduction. Baroreflex dysfunction makes hemodynamics sensitive to volume load. We hypothesized that baroreflex failure plays a pivotal role in the pathogenesis of HFpEF. Method and results In 5 anesthetized Sprague-Dawley rats with normal left ventricular (LV) function, we vascularily isolated bilateral carotid sinuses and controlled carotid sinus pressure (CSP) by a servo-controlled piston pump. We mimicked the normal baroreflex (NORMAL) by matching the CSP to arterial pressure and the baroreflex failure (FAILURE) by keeping CSP at a constant value. We infused dextran stepwise and measured left atrial pressure (LAP) and aortic pressure. We estimated the infused volume (∆V) and aortic pressure at which LAP reached 20 mmHg. In comparison with NORMAL, FAILURE markedly decreased ΔV (17.22±1.91 vs. 11.16±1.58 ml/kg, p<0.01), while increased aortic pressure (151.4±18.8 vs. 178.8±17.8 mmHg, p<0.05). Since the difference of ΔV (~6.0 ml/kg) reaches 1/3 of physiological stressed volume, baroreflex failure has major impact on the volume tolerance. Conclusion Baroreflex failure would make patients extremely sensitive to volume overload and susceptible to pulmonary edema irrespective of LV function.