The hypothalamo-pituitary-adrenal axis and sympathetic nervous system (SNS) interact to maintain cardiovascular and metabolic homeostasis, especially during stress. Pima Indians have a low SNS activity, which may contribute to both their increased risk of obesity and reduced risk of hypertension. Although glucocorticoids inhibit SNS activity, Pima Indians are not hypercortisolemic compared with Caucasians. This does not exclude the possibility that the SNS is more responsive to an inhibitory effect of cortisol in the former than in the latter group. We measured fasting plasma ACTH and cortisol and muscle SNS activity [muscle sympathetic nervous system activity (MSNA), microneurography] in 58 males [27 Pimas/31 Caucasians]. Seven Pimas and 12 Caucasians were randomized to a double-blind, placebo-controlled, cross-over study to examine the effect of overnight partial chemical adrenalectomy (metyrapone) followed by cortisol replacement (hydrocortisone) on plasma ACTH, cortisol, and MSNA. There were no ethnic differences in fasting plasma ACTH or cortisol, but MSNA adjusted for percent body fat was lower in Pimas than in Caucasians (P < 0.006). No correlation was found between fasting cortisol and basal MSNA. Administration of metyrapone did not lead to significant changes in MSNA. In response to a hydrocortisone infusion, MSNA decreased in Pima Indians (P = 0.03) but not in Caucasians (P = 0.7). Our data indicate that the low SNS activity that predisposes Pima Indians to obesity is not due to a tonic inhibitory effect of cortisol. However, an acute release of cortisol is likely to more effectively contain sympathoexcitation during stress in Pima Indians than in Caucasians, which may be an important mechanism of cardioprotection in this Native American population.