MK-912, a new alpha 2-adrenoceptor antagonist, was assessed in six volunteers by use of antagonism of the effects of intravenous clonidine as the main index of response. Subjects received single doses of either 0.2 or 2 mg of orally administered MK-912 or placebo in a randomized, double-blind, balanced, crossover design. Clonidine was infused intravenously over 10 minutes, 1 hour after dosing, and observations were made for 8 hours. The 2 mg dose of MK-912 significantly inhibited the clonidine-induced hypotension, bradycardia, xerostomia, and increase in plasma glucose concentrations that were observed during the placebo treatment period (p less than 0.05). The peak elevation in plasma growth hormone that was produced by clonidine on the day the placebo was given was inhibited an average of 87% by the 2 mg dose of MK-912 (p less than 0.01). Although there was a trend toward antagonism of clonidine by the 0.2 mg dose of MK-912, statistically significant differences from placebo were not consistently demonstrated for most parameters. However, a mean 59% inhibition of the clonidine-induced peak elevation of plasma growth hormone was observed (p less than 0.05). Oral MK-912 almost completely inhibits the effect of 200 micrograms of intravenous clonidine in human subjects, which is consistent with its role as a potent alpha 2-antagonist over the dose range of 0.2 to 2.0 mg.