Objective: Because sympathetic nervous system activity plays a detrimental role in metabolic and cardiovascular health, this study compared the effects of a centrally acting sympatholytic agent, the effects of a weight loss (WL) program using a low-calorie diet, and the effects of a combination of both. Methods: Young (18-30 years) male subjects with overweight (BMI>25 kg/m2) were allocated to a WL program (n=10), a moxonidine treatment course (M; n=10, 0.4 mg/d), a combination of both (WL+M; n=11), or to a control (C) group (n=6) for 6 months. Muscle sympathetic nerve activity (MSNA), endothelial function, renal function (Cockcroft-Gault formula), and the metabolic profile were assessed before and after intervention. Results: WL occurred in the WL and WL+M groups (-7.6±1.9 kg, P<0.001 in both). MSNA and systolic blood pressure decreased similarly in the WL, M, and WL+M groups (by ∼10 bursts/min, P<0.001, and by ∼9 mmHg, P<0.05). All other parameters for the WL, C, and M groups remained unchanged. In the WL+M group, decreased total cholesterol (-0.78±0.23 mmol/L, P<0.001), decreased low-density lipoprotein cholesterol (-0.49±0.16 mmol/L, P<0.01), decreased insulin (-6.5±2.8 mmol/L, P<0.05), and attenuated glomerular hyperfiltration (-19±5mL/min, P<0.01) occurred. Conclusions: The combination of moxonidine with a WL program has beneficial effects on aspects of the metabolic profile and end organ damage in young males with overweight.