Heart rate, blood pressure, and subjective stress ratings were recorded from 36 healthy normotensive students at three points in time: during a drug-free baseline, during a baseline 2 h after ingesting single oral doses of atenolol (75 mg), metoprolol (150 mg), or lactate placebo, and during a subsequently administered mental arithmetic test. Both beta-blockers equally reduced baseline heart rate and heart rate response to arithmetic, but subjective stress rating increases to arithmetic were greater for atenolol than for placebo and metoprolol. These results are contrary to peripheral theories of anxiety regulation. While the hydrophilic atenolol barely penetrates the blood-brain barrier, the lipophilic metoprolol can exert direct CNS effects in addition to its peripheral actions. Central stress-dampening effects of lipophilic beta-blockers may override peripheral baroreceptor-mediated stress-promoting effects.