The role of the sympathetic nervous system (SNS) in polycystic ovary syndrome (PCOS) is emerging. Previous studies support increased SNS activity in PCOS, potentially contributing to metabolic features. Moxonidine is a second-generation imidazoline I1 agonist inhibiting sympathetic outflow at the level of rostral ventrolateral medulla with known beneficial effects on hypertension, insulin sensitivity, dyslipidemia and inflammation. This study aimed to explore modification of SNS activity for the first time in PCOS. We hypothesized moxonidine will modify elevated SNS activity and downstream metabolic abnormalities in PCOS. 51 premenopausal women with PCOS were recruited, from a community setting, in a double blind placebo controlled clinical trial. 48 women were weaned off any interacting medication for 3 months, then randomized to moxonidine (0.2mg daily initially, up titrated to 0.4mg daily in 2 weeks) (n=23 ) or placebo (n=25) for 3 months. Multiunit muscle SNS activity (by microneurography), heart rate variability (HRV) and endothelial function (ischaemic reactive hyperaemia index (RHI) using EndoPAT) were examined. Fasting lipids, serum androgens and inflammatory markers were measured and an oral glucose tolerance test was performed to quantify IR using HOMA-IR pre and post intervention. 43 women (mean age: 29.8±5.9 years, mean BMI: 29.0±5.4 kg/m2) completed the trial (19 moxonidine, 24 placebo). Mean percentage change from baseline in MSNA (-10±23% vs -10±29% bursts per minute,P=NS), HRV (14±26% vs 14±41%nu in low frequency component,P=NS) and endothelial function (7±44% vs 15±45% in RHI,P=NS) did not differ significantly between two groups. hs-CRP reduced in moxonidine group (-26±37% vs 26±82%,p=0.012) and triglyceride reduced in placebo group (-4±29% vs 19±33%,p=0.027) which remained significant after adjustment for change in BMI. Change in blood pressure, HOMA-IR, and androgens did not differ between the two groups. Central sympathoinhibition with moxonidine does not modify higher SNS activity and downstream metabolic abnormalities in PCOS. Sympathoexcitation in PCOS may be driven peripherally or from other brain regions with further research needed.