The sympathetic nervous system is recognized to play a role in the etiology of animal and possibly human obesity through its impact on energy expenditure and/or food intake. We, therefore, measured fasting muscle sympathetic nerve activity (MSNA) in the peroneal nerve and its relationship with energy expenditure and body composition in 25 relatively lean Pima Indian males (means +/- SD; 26 +/- 6 yr, 82 +/- 19 kg, 28 +/- 10% body fat) and 19 Caucasian males (29 +/- 5 yr, 81 +/- 13 kg, 24 +/- 9% body fat). 24-h energy expenditure, sleeping metabolic rate, and resting metabolic rate were measured in a respiratory chamber, whereas body composition was estimated by hydrodensitometry. Pima Indians had lower MSNA than Caucasians (23 +/- 6 vs 33 +/- 10 bursts/min, P = 0.0007). MSNA was significantly related to percent body fat in Caucasians (r = 0.55, P = 0.01) but not in Pimas. MSNA also correlated with energy expenditure adjusted for fat-free mass, fat mass, and age in Caucasians (r = 0.51, P = 0.03; r = 0.54, P = 0.02; and r = 0.53, P = 0.02 for adjusted 24-h energy expenditure, sleeping metabolic rate, and resting metabolic rate, respectively) but not in Pima Indians. In conclusion, the activity of the sympathetic nervous system is a determinant of energy expenditure in Caucasians. Individuals with low resting MSNA may be at risk for body weight gain resulting from a lower metabolic rate. A low resting MSNA and the lack of impact of MSNA on metabolic rate might play a role in the etiology of obesity in Pima Indians.