Background: Glucose ingestion stimulates sympathetic nervous system (SNS) activity in lean subjects, whereas blunted responses have been reported in the obese. Objective: The objective was to investigate the impact of insulin resistance on the SNS response to oral glucose. Design: Nineteen insulin-resistant (IR) and 12 insulin-sensitive (IS) obese subjects with the metabolic syndrome and matched for age, sex, and blood pressure participated. Simultaneous measurements of muscle sympathetic nerve activity (MSNA) by microneurography, whole-body norepinephrine spillover rate, cardiac baroreflex sensitivity (BRS), calf blood flow, and arterial blood pressure were made at baseline and 30, 60, 90, and 120 min after a 75-g glucose load. Results: IR subjects had a higher insulin area under the curve from 0 to 120 min (AUC 0-120: 13,468 ± 677 compared with 6399 ± 612 mU/L·min; P < 0.001), glucose AUC0-120 (P < 0.05), and resting MSNA (41 ± 3 compared with 31 ± 3 bursts/min; P = 0.03) than did IS subjects. MSNA and the norepinephrine spillover rate increased from baseline (by 29 ± 7% and 40 ± 13%, respectively; P ≤ 0.001 for both) in IS subjects after the glucose load. In contrast, there was a blunted and delayed sympathetic response in IR subjects. Cardiac BRS and diastolic blood pressure decreased, whereas calf blood flow increased after the glucose load and by a similar magnitude in both groups (P < 0.01). Body mass index, abdominal fat, and insulin AUC0-120 were independent (inverse) predictors of the SNS response. Conclusions: IR subjects with the metabolic syndrome have a blunted SNS response to oral glucose compared with IS subjects with the metabolic syndrome, which is related to central adiposity and the insulin response but not to differences in skeletal muscle vasodilation or BRS.