First-generation antihistamines have potency, pharmacokinetic, and cost advantages compared with nonsedating second-generation antihistamines. Bedtime dosing of hydroxyzine was investigated as a dosing strategy to minimize reaction time degradation and adverse subjective symptoms previously documented for hydroxyzine in divided doses. Hydroxyzine, 50 mg qhs, was compared with terfenadine, 60 mg bid, in this double-blind, placebo-controlled crossover study of 15 healthy, asymptomatic adults. Computer-based eye-hand reaction time tests of simple reaction time (SRT) and choice reaction time (CRT) were not statistically different among the three drugs. Drowsiness, dry mouth, and irritability were significant for hydroxyzine (P = .0001, .001 and .02, respectively) compared with terfenadine or placebo, but less than seen in a previous study of hydroxyzine, 25 mg bid. Symptom scores with terfenadine were comparable to placebo. Histamine skin test wheal and flare were both significantly and comparably suppressed by hydroxyzine and terfenadine (P = .0001). While wheal suppression by hydroxyzine was universal, four of the 15 subjects showed little or no suppression with terfenadine (P = .03). Although bedtime dosing of hydroxyzine did not eliminate subjective symptoms, it maintained skin H1-receptor antagonism the following morning and alleviated the prolongation of reaction times previously reported with hydroxyzine in divided doses. The significant adverse subjective symptoms and psychomotor performance degradations caused by first-generation antihistamines can be mitigated by creative dosing schedules.