Heart transplantation does not normalize exercise capacity or the ventilatory response to exercise. We hypothesized that excessive muscle reflex activity, as assessed by the muscle sympathetic nerve activity (MSNA) response to handgrip exercise, persists after cardiac transplantation and that this mechanism is related to exercise hyperpnea in heart transplant recipients (HTRs). We determined the MSNA, ventilatory and cardiovascular responses to isometric and dynamic handgrips in 11 HTRs and 10 matched control subjects. Handgrips were followed by a post-handgrip ischemia in order to isolate the metaboreflex contribution to exercise responses. HTRs and control subjects also underwent recordings during isocapnic hypoxia, and a maximal, symptom limited, cycle ergometer exercise test. HTRs had higher resting MSNA (p<0.01) and heart rate (p<0.01) than the control subjects. Isometric handgrip increased MSNA in HTRs more than in the controls (p=0.003). Dynamic handgrip increased MSNA only in HTRs. During post-handgrip ischemia, MSNA and ventilation remained more elevated in HTRs (p<0.05). The MSNA and ventilatory responses to hypoxia were also higher in HTRs (both p<0.04). In HTRs, metaboreflex overactivity was related to the ventilatory response to exercise, characterized by the regression slope relating ventilation to CO2 output (r=+0.8; p<0.05) and a lower peak ventilation (r=+0.81; p<0.05) during cycle ergometer exercise tests. However, increased chemoreflex sensitivity (r=+0.91; p<0.005), but not metaboreflex activity accounted for the lower peak ventilation during exercise in a stepwise regression analysis. In conclusion, heart transplantation does not normalize muscle metaboreceptor activity; both increased metaboreflex and chemoreflex control are related to exercise intolerance in HTRs.