BACKGROUND: Obesity and atrial fibrillation (AF) are public health issues with significant consequences. OBJECTIVES: This study sought to delineate the development of global electrophysiological and structural substrate for AF in sustained obesity. METHODS: Ten sheep fed ad libitum calorie-dense diet to induce obesity over 36 weeks were maintained in this state for another 36 weeks; 10 lean sheep with carefully controlled weight served as controls. All sheep underwent electrophysiological and electroanatomic mapping; hemodynamic and imaging assessment (echocardiography and dual-energy x-ray absorptiometry); and histology and molecular evaluation. Evaluation included atrial voltage, conduction velocity (CV), and refractoriness (7 sites, 2 cycle lengths), vulnerability for AF, fatty infiltration, atrial fibrosis, and atrial transforming growth factor (TGF)-beta1 expression. RESULTS: Compared with age-matched controls, chronically obese sheep demonstrated greater total body fat (p <0.001); LA volume (p <0.001); LA pressure (p <0.001), and PA pressures (p <0.001); reduced atrial CV (LA p <0.001) with increased conduction heterogeneity (p <0.001); increased fractionated electrograms (p <0.001); decreased posterior LA voltage (p <0.001) and increased voltage heterogeneity (p <0.001); no change in the effective refractory period (ERP) (p > 0.8) or ERP heterogeneity (p > 0.3). Obesity was associated with more episodes (p = 0.02), prolongation (p = 0.01), and greater cumulative duration (p = 0.02) of AF. Epicardial fat infiltrated the posterior LA in the obese group (p <0.001), consistent with reduced endocardial voltage in this region. Atrial fibrosis (p = 0.03) and TGF-beta1 protein (p = 0.002) were increased in the obese group. CONCLUSIONS: Sustained obesity results in global biatrial endocardial remodeling characterized by LA enlargement, conduction abnormalities, fractionated electrograms, increased profibrotic TGF-beta1 expression, interstitial atrial fibrosis, and increased propensity for AF. Obesity was associated with reduced posterior LA endocardial voltage and infiltration of contiguous posterior LA muscle by epicardial fat, representing a unique substrate for AF.