The role of the sympathetic nervous system in the systemic hemodynamic and regional blood flow responses to hypoxia was studied in awake dogs by pre-exposing the animals to phentolamine alone (alpha block) or to phentolamine plus propranolol (alpha + beta block). Hypoxia was produced by switching from room air to either an 8% or 5% oxygen-nitrogen mixture. During 8% oxygen breathing, cardiac output, heart rate, left ventricular dP/dt, dP/dt/P, myocardial oxygen consumption, and myocardial blood flow increased, and both total peripheral and coronary vascular resistance fell. These changes were similar in all groups with and without adrenergic blockade. However, during 5% oxygen breathing, the rises in cardiac output, heart rate, left ventricular dP/dt, myocardial oxygen consumption, and myocardial blood flow and the decrease in coronary vascular resistance were less marked in the group given alpha + beta block than the intact animals or group given alpha block. Coronary blood flow correlated with myocardial metabolic demands. Adrenal and skeletal muscle blood flows increased during hypoxia. Breathing 5% oxygen also increased flow to the brain, but renal and splanchnic flows showed only minor changes. These changes in organ vascular resistance were unaffected by the adrenergic blockade. Our results indicate that although the sympathetic nervous system plays an important role in the systemic hemodynamic responses to hypoxia, the dominant local metabolic factors probably are primarily responsible for hypoxic vasodilation in the awake dog.