Adiponectin is an anti-inflammatory, antiatherogenic adipokine elevated in heart failure (HF) that may protect against endothelial dysfunction by influencing underlying nitric oxide bioavailability. In this study, we examine the relationship between plasma adiponectin levels and measures of nitric oxide bioavailability and myocardial performance in patients with chronic systolic HF. In 139 ambulatory patients with stable, chronic systolic HF (left ventricular [LV] ejection fraction ≤40%, New York Heart Association class I to IV), we measured plasma levels of adiponectin, asymmetric dimethylarginine (ADMA), and global arginine bioavailability (GABR), and performed comprehensive echocardiography with assessment of cardiac structure and performance. Adverse events (all-cause mortality or cardiac transplantation) were prospectively tracked for a median of 39 months. Plasma adiponectin levels directly correlated with plasma ADMA levels (Spearman'sr= 0.41,P< 0.001) and aminoterminal pro-B-type natriuretic peptide (NT-proBNP) levels (r= 0.55,P< 0.001), inversely correlated with GABR (r= −0.39,P< 0.001), and were not associated with high-sensitivity C-reactive protein (P= 0.81) or myeloperoxidase (P= 0.07). Interestingly, increased plasma adiponectin levels remained positively correlated with plasma ADMA levels only in patients with elevated NT-proBNP levels (r= 0.33,P= 0.009). Higher plasma adiponectin levels were associated with worse LV diastolic dysfunction (rank sumsP= 0.002), right ventricular (RV) systolic dysfunction (rank sumsP= 0.002), and RV diastolic dysfunction (rank sumsP= 0.011), but not after adjustment for plasma ADMA and NT-proBNP levels. Plasma adiponectin levels predicted increased risk of adverse clinical events (hazard ratio, 95% confidence interval 1.45 [1.02-2.07],P= 0.038) but not after adjustment for plasma ADMA and NT-proBNP levels, or echocardiographic indices of diastolic or RV systolic dysfunction. In patients with chronic systolic HF, adiponectin production is more closely linked with nitric oxide bioavailability than inflammation, and appears to be more robust in the setting of cardiac dysfunction or elevated natriuretic peptide levels.