Objective: To assess the association between adiponectin and incident heart failure (HF). Design and Methods: In the current ancillary study to the Physicians' Health Study (PHS), we used a prospective nested case-control design to examine whether plasma adiponectin concentration was related to the risk of HF. We selected 787 incident HF cases and 787 matched controls for the current analysis. Each control was selected using a risk set sampling technique at the time of the occurrence of the index case and matched on year of birth, age at blood collection, and race. Adiponectin was measured using enzyme-linked immunosorbent assay. HF occurrence was self-reported in annual follow-up questionnaire. Validation of self-reported HF in this cohort has been published. Results: The mean age was 58.7 years. In a conditional logistic regression adjusting for age, race, time of blood collection, year of birth, hypertension, atrial fibrillation, smoking, alcohol intake, and exercise, estimates of the relative risk (95% confidence interval) were 1.0 (reference), 0.74 (0.53-1.04), 0.67 (0.48-0.94), 0.70 (0.50-0.99), and 0.92 (0.65-1.30) from the lowest to the highest quintile of adiponectin, respectively, P for quadratic trend 0.004. Additional adjustment for potential mediating factors including diabetes, C-reactive protein, and BMI led to the attenuation of the estimate of effect (1.0 (reference), 0.81 (0.57-1.15), 0.75 (0.53-1.06), 0.83 (0.58-1.18), and 1.26 (0.87-1.81) across consecutive quintiles of adiponectin). Conclusions: Our data are consistent with a J-shaped association between total adiponectin and the risk of HF among US male physicians.