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Afferent baroreflex failure is most often due to damage of the carotid sinus nerve because of neck surgery or radiation. The clinical picture is characterized by extreme blood pressure lability with severe hypertensive crises, hypotensive episodes, and orthostatic hypotension, making it the most difficult form of hypertension to manage. There is little evidence-based data to guide treatment. Recommendations rely on understanding the underlying pathophysiology, relevant clinical pharmacology, and anecdotal experience. The goal of treatment should be improving quality of life rather than normalization of blood pressure, which is rarely achievable. Long-acting central sympatholytic drugs are the mainstay of treatment, used at the lowest doses that prevent the largest hypertensive surges. Short-acting clonidine should be avoided because of rebound hypertension, but can be added to control residual hypertensive episodes, often triggered by mental stress or exertion. Hypotensive episodes can be managed with countermeasures and short-acting pressor agents if necessary.