To determine the effects of nicotine HCl on the cerebral circulation of the cat, without the complicating actions of the drug at other sites in the body, the drug was perfused at concentrations of 1, 10 and 100 μg/ml through a vascularly isolated, perfused in situ cat brain preparation. Cats having selective section of cranial nerves 9, 10, 11 and 12 and the cervical sympathetic trunks comprised various experimental groups. Nicotine was also perfused through an isolated, denervated hindlimb of the same cat for comparative purposes. Nicotine caused only a mild and transient vasoconstriction of the cerebral circulation, mediated primarily by stimulation of the superior cervical ganglia, and a small direct cerebral vasoconstrictor component. An acute tolerance to the cerebral vasoconstrictor effects of repeated increments of nicotine was also observed. The cerebral vasoconstrictor effect of nicotine was diminished in the presence of intact vagi, suggesting a cerebral vasodilator role for these nerves. In contrast, the effect of nicotine on the denervated hindlimb vasculature was a weak but sustained vasodilation. The mechanism of action of nicotine on the cerebral circulation is discussed along with the relevance of these findings to the potential health hazards of tobacco smoking in individuals with cerebrovascular insufficiency.