The basis of the vasodepressor response in patients with carotid sinus hypersensitivity (CSH) is unknown, and prevention of recurrent vasodepressor-induced hypotension in these patients has not been possible. In this study we assessed the effectiveness of atrioventricular sequential pacing and pharmacologic interventions in the prevention of carotid sinus massage (CSM)-induced vasodepressor responses in eight patients with CSH. Maintenance of constant heart rate (80 beats/min) and atrioventricular synchrony (atrioventricular interval 150 msec) with sequential pacing did not significantly alter mean CSM-induced fall in systolic pressure (CSM control, -60 ± 12 mm Hg vs CSM with atrioventricular sequential pacing, -48 ± 19 mm Hg). Similarly, neither pharmacologic muscarinic blockade nor combined muscarinic and β-adrenergic blockade significantly attenuated CSM-induced fall in systolic pressure (CSM with atropine, -43 ± 16 mm Hg; CSM with atropine plus propranolol, -47 ± 18 mm Hg; both p = NS vs atrioventricular sequential pacing alone). On the other hand, intravenous norepinephrine and oral ephedrine blunted the CSM-induced drop in systolic pressure (CSM with norepinephrine, -19 ± 12 mm Hg; CSM with ephedrine, -21 ± 11 mm Hg; both p < .01 vs atrioventricular sequential pacing alone). Thus, vasodepressor responses were not prevented by control of heart rate, maintenance of atrioventricular synchrony, pharmacologic muscarinic blockade, or combined muscarinic and β-adrenergic blockade, but were attenuated by drugs believed to be predominantly α-adrenergic agonists. Consequently, atrioventricular sequential pacing alone may be inadequate to prevent hypotension in patients with pronounced vasodepressor responses, whereas administration of vasoconstrictors such as ephedrine may diminish symptoms.