To test whether a beta-blocker's pharmacokinetics has an effect on the development of the beta-blocker withdrawal syndrome, we compared response to exercise and isoproterenol after abrupt withdrawal of two beta-blockers, one with a short half-life (propranolol) and one with a long half-life (nadolol). Eight normal males participated in the randomized cross-over trial. They took propranolol, 40 mg every 6 hours for 6 days, and nadolol, 80 mg daily for 7 days. Exercise- and isoproterenol-induced changes in heart rate and pulse pressure were significantly less than control values during treatment with both drugs (p less than 0.05). Significant hypersensitivity of heart rate response was seen on days 2, 3, and 7 after propranolol withdrawal (p less than 0.05) and on day 6 after nadolol withdrawal (p less than 0.005). Hypersensitive responses to isoproterenol were seen after propranolol withdrawal; no evidence of hypersensitivity to isoproterenol was seen after nadolol withdrawal. The area under the heart rate response, time curve after nadolol withdrawal was significantly less than that after propranolol withdrawal (20.3 beats/min.day vs 44.9 beats/min.day, respectively, (p less than 0.05). There was a significant inverse correlation between the degree of hypersensitivity and nadolol pharmacokinetic half-life (r = -0.80, p less than 0.02). We conclude that abrupt withdrawal of a beta-blocker with a long half-life may protect against the development of the beta-blocker withdrawal syndrome.