Clonidine at doses of 0.5-1.0 mg/kg i.p. produced an initial rise followed by a sustained fall in blood pressure. The initial pressor response became more marked and the onset of hypotensive effect was delayed as the dose was increased to large doses such as 10-50 mg/kg given intraperitoneally. The heart rate was markedly reduced soon after clonidine administration and the bradycardia lasted for more than 2 hours. Both the initial pressor and subsequent hypotensive effects of clonidine were reduced by pretreatment with phentolamine, the initial pressor effects were suppressed by propranolol which did not affect the hypotensive effects. This initial pressor effect was potentiated while the hypotensive effect was reduced after bilateral vagotomy and pretreatment with either 6-hydroxydopamine or atropine. The bradycardia was significantly reduced by propranolol, atropine and bilateral vagotomy. Central sympathetic as well as parasympathetic mechanisms may be involved in cardiovascular changes after large doses of clonidine in urethanized mice.