The role of central serotonergic neurons in circulatory control was studied in rabbits given intracisternal injections of 5, 6-dihydroxytryptamine (5, 6-DHT, 300 µg/kg) to cause degeneration of central serotonergic nerve terminals and depletion of central serotonin stores. In normal rabbits, intracisternally administered 5.6-DHT produced decreases in mean arterial blood pressure (11%, P < 0.001) and heart rate (9%, P < 0.001) that were maximum 1 week after injection. Central serotonin levels were reduced to less than 50% in the spinal cords of the rabbits treated with 5, 6-DHT compared with the levels in vehicle-injected controls. Pretreatment with intracisternally administered 5, 6-DHT completely prevented the sustained increases in mean arterial blood pressure and heart rate seen after sinoaortic denervation in control rabbits. In rabbits with neurogenic hypertension following sinoaortic denervation, treatment with intracisternally administered 5, 6-DHT caused a prompt, persistent reduction in mean arterial blood pressure and heart rate. Intracisternally administered 5, 6-DHT failed to interfere with the development or the maintenance of the hypertension that follows bilateral wrapping of the kidneys with cellophane. This study suggests that central serotonergic neurons participate in the baroreceptor reflex arc, possibly at the bulbospinal level. The integrity of these neurons appears to be necessary for the development of sustained neurogenic hypertension following sinoaortic denervation but to be of minimum importance in experimental renal hypertension in the rabbit.