Twelve healthy subjects with atopy received single doses of hydroxyzine, 25 mg, its metabolite cetirizine, 10 and 20 mg, and placebo in a four-way crossover study randomized by Latin square design. Skin wheal response to histamine, psychomotor effects, and serum concentrations of each drug were measured for 36 hours after each dose. Central nervous system (CNS) effects were measured with critical flicker frequency, Stroop word testing, and visual analog scales. All three active treatments (cetirizine, 10 mg, cetirizine, 20 mg, and hydroxyzine) produced an equivalent suppression of skin wheal response to histamine that was significantly greater than placebo (P less than 0.01). Hydroxyzine produced a significant change compared with placebo in all three CNS parameters. Neither cetirizine, 10 mg, nor cetirizine, 20 mg, produced any significant change in CNS parameters. Both the intensity and time course of CNS effects were related significantly (P less than 0.05) to hydroxyzine concentrations. The CNS changes measured after oral hydroxyzine are the result of the parent drug, whereas its metabolite cetirizine when administered alone produced significant antihistaminic effects without CNS changes.