BACKGROUND: The underlying mechanism of atrial fibrillation (AF) in association with hypoxia remains unclear. This study aimed to investigate the AF vulnerability in an acute intermittent hypoxia model and ascertained the mechanism. METHODS AND RESULTS: In 15 anesthetized open-chest dogs (10 experimental and 5 control), multiple-electrode catheters were sutured to the surface of atria, pulmonary veins and superior vena cava. The ventilators were adjusted to simulate the intermittent hypoxia for 1h. The heart rate, blood pressure, blood gas, heart rate variability (HRV), effective refractory period (ERP) and window of vulnerability (WOV) as a measure of AF inducibility were measured. As the hypoxia prolonged, the pH, PaO2 and SaO2 progressively decreased, while the PaCO2 increased (P<0.05 for all). In the first 30 min of hypoxia, the HRV indexes associated with sympathetic activity (LF) and parasympathetic activity (HF) both increased but the ratio of LF/HF stayed unchanged. The ERP and WOV were not affected. In the second 30 min of hypoxia, the parasympathetic activity (HF) further increased while the ratio of LF/HF subsequently decreased. Meanwhile, the ERP shortened, and the WOV significantly increased (P<0.05 for all). All the changes that were caused by hypoxia were reversed by 1-h re-ventilation. CONCLUSIONS: AF vulnerability increases in the acute intermittent hypoxia model in which autonomic imbalance may play an important role. The treatment targeting autonomic imbalance may be considered when encountering this kind of AF such as in sleep apnea.