AbstractSince most classical (first‐generation) antihistamines have undesirable sedative effects on the central nervous system (CNS), newer (second‐generation) antihistamines have been developed to relieve the sedative effects and to improve the patient's quality of life. However, the psychomotor profiles of second‐generation antihistamines are not fully elucidated. In this randomized, double‐blind, crossover study, the acute effects of single doses of second‐generation antihistamines, fexofenadine (120 mg) and olopatadine (10 mg), on cognitive and psychomotor performance were investigated in comparison with those of placebo and d‐chlorpheniramine (4 mg), a first‐generation antihistamine, using objective and subjective assessments, in 11 healthy Japanese volunteers. In a battery of psychomotor tests, d‐chlorpheniramine impaired tracking ability in the compensatory tracking task and caused a reduction in behavioural activity as continuously measured by wrist actigraphy. Olopatadine, like d‐chlorpheniramine, reduced the behavioural activity, while fexofenadine had no effect in any of the tests. No significant changes in the subjects' self‐ratings of drowsiness were found with the three antihistamines. These results suggest that d‐chlorpheniramine and olopatadine, but not fexofenadine, produce sedative effects on psychomotor performance, and that the CNS profile of fexofenadine is different from that of olopatadine. Copyright © 2003 John Wiley & Sons, Ltd.