Context: Sympathetic nervous system (SNS) overactivity participates in both the pathogenesis and adverse clinical complications of metabolic syndrome (MetS) obesity. Objective: We conducted a prospective lifestyle intervention trial to compare the effects of active weight loss and extended weight loss maintenance on SNS function and MetS components. Methods: Untreated subjects (14 males, four females; mean age, 53±1 yr; body mass index, 30.9±0.9 kg/m2) who fulfilled Adult Treatment Panel III criteria were randomized to 12-wk hypocaloric diet alone (n = 8) or together with aerobic exercise training (n = 10). This was followed by a 4-month weight maintenance period. Measurements of muscle sympathetic nerve activity (MSNA) by microneurography, whole-body norepinephrine kinetics, substrate oxidation by indirect calorimetry, baroreflex sensitivity, plasma renin activity (PRA), and MetS components were performed. Results: Body weight decreased by 9.3±0.8% at wk12 (P<0.001), and this was maintained. During active weight loss, norepinephrine spillover rate decreased by 23±16% (P=0.004), MSNA by 25±3 bursts per 100 heartbeats (P < 0.001), and PRA by 0.25 ± 0.09 ng/ml • h (P = 0.007), whereas baroreflex sensitivity increased by 5.2 ± 2.2 msec/mm Hg (P = 0.005). After weight maintenance, beneficial effects of weight loss on norepinephrine spillover rate were preserved, whereas PRA and MSNA rebounded (by 0.24±0.11 ng/ml • h, P=0.02; and 20±5 bursts/100 heartbeats, P=0.0003), and baroreflex sensitivity was attenuated. Conclusions: Divergent effects of successful weight loss maintenance on whole-body norepinephrine spillover rate and MSNA suggest organ-specific differentiation in SNS adaptation to weight loss under conditions of negative vs. stable energy balance.