The combined effects of alcohol and cigarette smoking on the cerebral circulation are unknown. The current study was designed (1) to compare the acute effects on cerebral vessels of cigarette smoking alone with those of alcohol plus cigarette smoking and (2) to clarify the mechanism or mechanisms underlying the cerebrovascular responses. In pentobarbital-anesthetized, mechanically ventilated Sprague-Dawley rats, we measured pial vessel diameters with the use of a cranial window preparation. Rats, pretreated with alcohol (n = 6; 1 g/kg/h, i.v.; 1-h infusion from t = -60 min to t = 0) or with saline (n = 6), were exposed to 60 puffs per minute of mainstream smoke from a 1 mg-nicotine cigarette. Inhalation of smoke caused pial arterioles to constrict at t = 30 s (8.4%) and, subsequently, to dilate (peak at t = 5-10 min; 18.7%). Pretreatment with alcohol caused pial vasodilation (14.0%), and, after inhalation of cigarette smoke, the pial vasodilation occurred earlier (peak at t = 1-5 min; 30.2%) and was larger, without an initial vasoconstriction. The plasma concentration of thromboxane (TX) B2 (a stable metabolite of TXA2) increased after this smoking, and alcohol pretreatment attenuated this increase (protocol as above). Cigarette smoking had a significant biphasic effect on cerebral arteriolar tone. However, alcohol suppressed the initial vasoconstriction, probably, at least in part, by attenuating the smoking-induced TXA2 production.