Guanethidine sulphate 5 and 40 mg/kg was administered intraperitoneally to adult rats for 4, 8, 14, and 28 days followed by discontinuation for 1 day, after administration for 28 days and additionally for 8, 14, 29, and 60 days. Under chloralose-urethane anaesthesia the mean arterial blood pressure and the mean heart rate were determined and the response of these parameters to intravenous noradrenaline 3-1600 ng was recorded. The blood pressure was not significantly changed after guanethidine 5 mg/kg, but lowered by 40 mg/kg, the decrease being reversible on discontinuation. The response of both parameters to noradrenaline was increased by guanethidine depending on the dose. The hypersensitivity was partly reversible on discontinuation, but a significantly increased sensitivity of the heart rate to noradrenaline was observed 60 days after discontinuation of guanethidine 40 mg/kg for 28 days. Histologically a profound loss of nerve cells of the superior cervical ganglion was observed following guanethidine 40 mg/kg, whereas no change was observed after 5 mg/kg. The present investigation has demonstrated that guanethidine 5 mg/kg does not induce histological or permanent haemodynamic changes, whereas 40 mg/kg for 28 days result in an incomplete sympathectomy accompanied by a partially irreversible hypersensitivity to noradrenaline. There is no simple relation between the loss of ganglion cells and the haemodynamic changes, and hence the hypersensitivity to noradrenaline is only in part due to the destruction of the postganglionic sympathetic neurone obtained by long term administration of large doses of guanethidine.