Decreases in systolic blood pressure during exercise may predispose to arrhythmias such as atrial fibrillation (AF) because of underlying abnormal autonomic tone. We examined the association between systolic blood pressure response and incident AF in 57,442 (mean age 54 ± 13 years, 47% women, and 29% black) patients free of baseline AF who underwent exercise treadmill stress testing from the Henry Ford ExercIse Testing project. Exercise systolic blood pressure response was examined as a categorical variable across clinically relevant categories (>20 mm Hg: referent; 1 to 20 mm Hg, and ≤0 mm Hg) and per 1-SD decrease. Cox regression, adjusting for demographics, cardiovascular risk factors, medications, history of coronary heart disease, history of heart failure, and metabolic equivalent of task achieved, was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between systolic blood pressure response and incident AF. Over a median follow-up of 5.0 years, a total of 3,381 cases (5.9%) of AF were identified. An increased risk of AF was observed with decreasing systolic blood pressure response (>20 mm Hg: HR 1.0, referent; 1 to 20 mm Hg: HR 1.09, 95% CI 0.99, 1.20; ≤0 mm Hg: HR 1.22, 95% CI 1.06 to 1.40). Similar results were obtained per 1-SD decrease in systolic blood pressure response (HR 1.08, 95% CI 1.04 to 1.12). The results were consistent when stratified by age, sex, race, hypertension, and coronary heart disease. In conclusion, our results suggest that a decreased systolic blood pressure response during exercise may identify subjects who are at risk for developing AF.