The role of endogenous opioids in aerobic fitness-induced decrements in cardiovascular stress reactivity was examined by comparing the effects of opioid antagonism with naltrexone on responses to stress in young adults with high versus low levels of aerobic fitness. Two hundred forty subjects were given an activity questionnaire and males with the highest (Fit) and lowest (Nonfit) aerobic activity profiles were recruited for maximal oxygen consumption (VO2max) treadmill testing and psychological stress testing (final sample N = 28). Heart rate and blood pressures were measured during performance on a computer-controlled arithmetic task after pretreatment with either naltrexone (Trexan, DuPont) or a placebo. During placebo challenges, Fit subjects, compared with Nonfit, showed lower heart rate reactivity during stress and lower mean arterial blood pressures immediately before and during recovery from stress. Naltrexone eliminated these reactivity differences by increasing heart rate reactivity and raising mean arterial blood pressure in Fit subjects. These data suggest that aerobic fitness is associated with enhanced opioidergic inhibition of circulatory stress reactivity. Opioidergic modulatory effects on stress reactivity may comprise an important mechanism in fitness-associated risk reduction for cardiovascular disease.