It is well known that the sedative properties of antihistamines can differ considerably between individual drugs. Several factors have been suggested to determine the presence, absence, and/or magnitude of sedation by antihistamines. Research has suggested that the sedative effects caused by central H1 blockade partly depend on the availability of histamine competing for the same receptor and that this competition is affected by a mechanism related to sleep. Consequently, the present study was designed to compare the effects of evening and morning doses of the first-generation antihistamine hydroxyzine on cognition. It was expected that the sedative effect of hydroxyzine would be apparent in the evening after an evening dose but would be smaller in the morning after a morning dose owing to the greater release of histamine shortly after awakening. Eighteen participants (9 females) participated in a placebo-controlled, randomized, double-blind 3-way crossover design. Performance was assessed using several psychomotor tests: that is, divided attention task, critical tracking task, stop signal task, the attention network test, and the experimental attention switch task. Results demonstrated that evening doses of hydroxyzine impaired performance on the divided attention and the attention network test. Impairment after morning doses was generally larger in magnitude and affected performance measures in all tasks. It is concluded that hydroxyzine-induced impairment at t(max) is more prominent after morning doses compared with evening doses and that the present study could not present direct evidence to substantiate the hypothesis that histamine availability inversely affects the magnitude of antihistamine impairment.