The disposition of the pharmacologically active 4‐hydroxypropranolol (HO‐P), its glucuronic acid conjugate (HO‐P‐G), and propranolol were compared after single intravenous and oral doses of propranolol in 6 normal subjects and after long‐term therapy in 32 patients with hypertension or coronary artery disease. The areas under the plasma concentration/time curves (AUC∞, ng · hr/ml) after 4‐mg intravenous doses of propranolol were 6.6 ± 2.2 (mean ± SEM) for HO‐P and 55 ± 11 for propranolol. After 20‐ and 80‐mg oral doses the AUC∞for HO‐P were 59 ± 9 and 162 ± 21 and for propranolol were 72 ± 9 and 306 ± 46. Peak HO‐P concentrations were reached at 1 to 1.5 hr after the oral doses. Although there was a rapid decline in plasma HO‐P between 1.5 and 3 hr when HO‐P‐G was still rising to levels above HO‐P levels 3.5‐ to 5‐fold, the apparent half‐lifes (t½s) after 3 hr were in the same range for HO‐P, HO‐P‐G, and propranolol (3.0 to 4.2 hr). While during long‐term therapy plasma HO‐P rose over the whole dose range (40 to 960 mg daily) in an apparently linear fashion, the HO‐P/propranolol plasma level ratio fell from 1.07 ± 0.13 at 40 mg daily to only 0.09 ± 0.01 at 640 mg daily. Plasma HO‐P‐G rose exponentially with dose and demonstrated significant cumulation. HO‐P and HO‐P‐G in urine accounted for about 9% of long‐term propranolol doses. This study suggests a significant contribution of HO‐P to pharmacologic effects, in particular at low single and long‐term oral doses of propranolol and saturation of naphthalene ring oxidation as a main determinant of propranolol bioavailabilit