Central cholinergic control of pulse rate and blood pressure has seldom been studied in humans. In the current study we contrasted the cardiovascular effects of the centrally acting cholinesterase inhibitor physostigmine, which increases central and peripheral acetylcholine levels, with those of saline placebo and with those of the non-centrally acting cholinesterase inhibitor neostigmine, which only increases peripheral acetylcholine levels. We found that physostigmine, in contrast to neostigmine and saline, caused significant and often profound increases in pulse rate and blood pressure levels in humans. Thus, we conclude that acetylcholine may have a role in central cardiovascular regulation in humans. We also found that administration of physostigmine may cause net increases in pulse of up to 74 beats/minute, systolic blood pressure increases of up to 50 mm Hg, and diastolic increases of up to 45 mm Hg. Such increases could be dangerous in elderly patients with concomitant cerebrovascular or coronary circulation disorders.