Middle cerebral artery (MCA) flow velocity was continuously monitored during smoking in an observational study (n = 14) using transcranial Doppler (TCD) ultrasonography. Cerebral autoregulatory vasodilator capacitance under inspired CO2 challenge was also measured before smoking and at peak smoking effect. Several puffs on a single lighted cigarette over a period of five minutes acutely increased MCA mean flow velocity in every subject (group mean increase: 19%, individual increases ranged 2-64%) with a response onset and offset detectable within several seconds of beginning and ending smoking. The mechanism for the increase in MCA flow velocities appeared to be independent of the CO2 autoregulatory mechanism. Gender subgroup analysis showed smoking acutely suppressed the CO2 vasodilator capacitance by 56% in men but only by 5% in women (p = 0.05). The magnitude of the acute smoking-induced increases in MCA flow velocities appeared to be independent of the estimated cigarette yields for nicotine, carbon monoxide, and "tar." Smoking in healthy subjects acutely increased MCA mean flow velocity, which may reflect a global increase in cerebral blood flow via complex influences on the cerebral autoregulation.