Polycystic ovary syndrome (PCOS) is associated with worsened metabolic risk factors attributed to the interrelated effects of insulin resistance (IR), hyperandrogenism, sympathetic nervous system (SNS) dysfunction and chronic low grade inflammation. HMW-adiponectin is inversely associated with IR and metabolic disorders. Lower HMW-adiponectin levels are reported in PCOS however the regulatory mechanisms remain unclear. We explored the regulatory mechanisms for HMW-adiponectin in a cross sectional study of 46 PCOS (Rotterdam criteria) and 23 control women recruited from the community. Fasting lipids, total testosterone, sex hormone binding globulin (SHBG), highly sensitive C-reactive protein, HMW-adiponectin, muscle sympathetic nerve activity (as burst frequency (bursts/min) on microneurography) were measured and an oral glucose tolerance test was performed with IR determined on Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). HMW-adiponectin was lower in PCOS after adjustment for age and BMI (2.2(2.3) µg/ml vs 3(2.5) µg/ml, adjusted p=0.047). HMW-adiponectin correlated with SHBG, HOMA-IR, fasting insulin, triglycerides, high density lipoprotein cholesterol (HDL-C) and free androgen index (FAI) in all participants (r=0.468 p<0.001, r=-0.429 p<0.001, r=-0.425 p<0.001, r=-0.324 p=0.008, r=0.347 p=0.005 and r=-0.456 p<0.001 respectively) and in PCOS (r=0.522 p<0.001, r=-0.476 p=0.001, r=-0.509 p<0.0001, r=-0.384 p=0.01, r=0.461 P=0.002 and r=-0.503 P<0.001 respectively). Metabolic syndrome was significantly associated with lower HMW-adiponectin levels in all participants (odds ratio 0.033, 95% CI 0.002, 0.498 p=0.014) and in PCOS (odds ratio 0.024, 95% CI 0.001, 0.652 p=0.027). Burst frequency was significantly lower in PCOS (25.7(10.5) vs 21.6(13.7) bursts per minute, p=0.037) and correlated significantly with HMW-adiponectin (r=-0.326 p=0.049). On multiple regression analysis burst frequency (B=-0.684 p=0.011) and SHBG (B=0.008 p<0.001) explained 40% of the variability in HMW-adiponectin in PCOS (Adjusted R2=0.406, overall p<0.001). This study shows novel associations between sympathetic activity, HMW-adiponectin and metabolic features in PCOS, suggesting that SNS is linked to and may modulate metabolic features in PCOS.