A cardiogenic hypertensive chemoreflex was studied in 38 anesthetized and three unanesthetized dogs. Serotonin (100 μg/ml) injected into either the left atrium or small branches of the proximal left coronary artery produced a maximal response, with 96 ± 18 mm Hg increment in mean aortic pressure within 6 ± 2 seconds, lasting about 1 min; a later phase of the same hypertension lasted 9 ± 5 minutes more and could partially be produced with serotonin injected into the thoracic aorta. Injections into the distal left coronary artery produced only the Bezold Jarisch reflex. Concomitant with the immediate hypertension there were vagal and sympathetic efferent effects in both the sinus node and the atrioventricular (A V) junction. Either of these effects could be selectively eliminated and the other augmented by direct local perfusion with an appropriate cholinergic (atropine 10 μg/ml) or adrenergic β receptor (propranolol 10 μg/ml) blocking agent. Bilateral vagotomy markedly attenuated but did not eliminate the acute hypertension, but it abolished both chronotropic and dromotropic effects. Phentolamine (2 mg/min i.v.) markedly diminished the hypertensive response. Guanethidine or reserpine pretreatment markedly diminished the hypertensive response; reserpine eliminated tne electrophysiologic effect but guanethidine did not. Infiltration of serotonin around the main left coronary partially reproduced the reflex, but similar infiltration of xylocaine hydrochloride blocked the reflex. Serial section histologic studies of the region around the main left coronary artery in seven dog hearts and nine human hearts demonstrated the presence of a small structure resembling a chemoreceptor; its blood supply originated from the left coronary artery. Some possible clinical implications are discussed.