First-generation H1-antagonist antihistamines, such as hydroxyzine, have the ability to cross the blood-brain barrier and cause sedation, which limits their usefulness in the treatment of allergic disorders. Cetirizine, a carboxylated metabolite of hydroxyzine, possesses the parent compound's antihistaminic activity but causes less sedation. We compared the activity of cetirizine at central H1 sites with that of hydroxyzine and terfenadine. We also compared the ability of cetirizine and three antihistamines to cross the blood-brain barrier. In each case we found that the drug's potency at H1 receptors in the central nervous system was similar to its activity in displacing H1 receptors in the lung. However, the selectivity for H1 receptors varied widely from drug to drug. Cetirizine did not bind at any of the receptors investigated, except H1 sites, even at concentrations as high as 10 mumol/L. Hydroxyzine and dexchlorpheniramine and, to a lesser extent, terfenadine crossed the blood-brain barrier in significant amounts. Cetirizine passed into the central nervous system only half as readily as terfenadine. These findings suggest that cetirizine's low incidence of sedative effects is most likely caused by its diminished potential to cross the blood-brain barrier and also may be partly the result of its greater selectivity for H1 receptors, compared with its effect at other receptors that may be involved in sedation.