Abstract Context Chronic glucocorticoids excess leads to morphological and functional cardiac alterations, a substrate for arrhythmias. Autonomous cortisol secretion (ACS) in adrenal incidentalomas is a model of chronic endogenous hypercortisolism. Objective To investigate prevalence and incidence of atrial fibrillation (AF) in a large cohort of patients with ACS. Design Retrospective study. Setting University hospital. Patients Patients evaluated between 1990 and 2018 for adrenal incidentalomas (n = 632), without pheochromocytoma, primary aldosteronism, Cushing syndrome, congenital adrenal hyperplasia, and adrenal malignancy. Cortisol after 1-mg dexamethasone suppression test < or > 50 nmol/L defined nonsecreting tumors (NST) (n = 420) and ACS (n = 212), respectively. Intervention Assessment of AF at baseline (n = 632) and during a median follow-up of 7.7 years retrospectively (NST, n = 249; ACS, n = 108). Comparison with general population. Main Outcome Measure Prevalence and incidence of AF. Results AF prevalence was higher in patients with ACS (8.5%) than NST (3.1%, P = 0.003) and the general population (1.7%; P < 0.001 vs ACS, P = 0.034 vs NST). The age-adjusted rate ratio to the general population was 1.0 for NST and 2.6 for ACS. AF was associated with ACS (odds ratio, 2.40; 95% confidence interval [CI], 1.07-5.39; P = 0.035). The proportion of patients with AF at last evaluation was higher in ACS (20.0%) than NST (11.9%; P = 0.026). ACS showed a higher risk of incident AF than NST (hazard ratio, 2.95; 95% CI, 1.27-6.86; P = 0.012), which was associated with post-dexamethasone cortisol (hazard ratio, 1.15; 95% CI, 1.07-1.24; P < 0.001), independently of known contributing factors. Conclusions Patients with adrenal incidentalomas and ACS are at risk of AF. Electrocardiogram monitoring may be recommended during follow-up.