1. Histamine H1 receptor occupancy in the human brain was measured in 20 healthy young men by positron emission tomography (PET) using [11C]-doxepin. 2. (+)-Chlorpheniramine, a selective and classical antihistamine, occupied 76.8 +/- 4.2% of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg. Intravenous administration of 5 mg (+)-chlorpheniramine almost completely abolished the binding of [11C]-doxepin to H1 receptors (H1 receptor occupancy: 98.2 +/- 1.2%). 3. Terfenadine, a nonsedative antihistamine, occupied 17.2 +/- 14.2% of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg. 4. There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject. 5. PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea-pig brain determined by in vivo binding techniques, although for the same H1 receptor occupancy the dose was less in human subjects than in guinea-pigs. 6. The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second-generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively.