Background-Heart failure is characterized by increased ventilation during exercise, which is positively related to increased peripheral and central chemoreceptor sensitivity. Heart transplantation does not normalize the ventilatory response to exercise, and its effects on the chemoreflex control of ventilation remain unknown. We tested the hypothesis that chemoreceptor sensitivity is increased in heart transplant recipients (HTRs) and linked to exercise hyperpnea. Methods and Results-We determined the ventilatory, muscle sympathetic nerve activity (MSNA), and circulatory responses to isocapnic hypoxia and hyperoxic hypercapnia 7Ϯ1 years after transplantation in 19 HTRs with a normal left ventricular ejection fraction of 60Ϯ2%. Results were compared with those of 11 closely matched referent subjects. Sixteen patients and 10 referent subjects also underwent cycle ergometer exercise tests. HTRs compared with referent subjects presented higher MSNA (52Ϯ4 versus 34Ϯ3 bursts/min; PϽ0.01) and heart rates (83Ϯ3 versus 68Ϯ3 bpm; PϽ0.01) during room air breathing. The ventilatory response to hypoxia was higher in HTRs than in referent subjects (PϽ0.01, ANOVA). The increase in MSNA also was more marked during hypoxia in the HTRs than in the referent group (PϽ0.05, ANOVA