There are conflicting reports for the role of endogenous opioids on sympathetic and cardiovascular responses to exercise in humans. A number of studies have utilized naloxone (an opioid receptor antagonist) to investigate the effect of opioids during exercise. In the present study, we examined the effect of morphine (an opioid receptor agonist) on sympathetic and cardiovascular responses at rest and during isometric handgrip (IHG). Eleven subjects performed 2 min of IHG (30% maximum) followed by 2 min of postexercise muscle ischemia (PEMI) before and after systemic infusion of morphine (0.075 mg/kg loading dose + 1 mg/hr maintenance) or placebo (saline) in double blinded experiments on separate days. Morphine increased resting muscle sympathetic nerve activity (MSNA; 17 ± 2 to 22 ± 2 bursts/min; P<0.01) and increased mean arterial blood pressure (MAP; 87 ± 2 to 91 ± 2 mmHg; P<0.02), but decreased heart rate (HR; 61 ± 4 to 59 ± 3; P<0.01). However, IHG elicited similar increases for MSNA, MAP, and HR between the control and morphine trial (Drug x Exercise interaction = NS). Moreover, responses to PEMI were not different. Placebo had no effect on resting, IHG, and PEMI responses. We conclude that morphine modulates cardiovascular and sympathetic responses at rest, but not during isometric exercise.