Background: Since all antihistamines are capable of crossing the blood-brain barrier, they may also cause sedation which may impair daily activities such as driving a car. The purpose of this review was to examine the effects of antihistamines on driving ability. Method: A literature search revealed 18 double-blind placebo-controlled clinical trials that applied the on-road highway driving test. In this test, subjects are instructed to drive 100-km on a public highway with a steady lateral position and a constant speed (95 km/h). Primary outcome measure is the Standard Deviation of Lateral Position (SDLP, cm), i.e. the weaving of the car. Results: The literature search yielded 18 clinical trials. At therapeutic doses, a single dose of diphenhydramine, emedastine and hydroxizine impaired driving comparable or greater than the effects of BAC 0.08%. Clemastine, triprolidine, mizolastine, acrivastine, dexchlorpheniramine CR and mequitazine impaired driving performance to the same extent as BAC 0.05%. For mizolastine significant impairment was only seen after higher than therapeutic doses. Results for cetirizine were mixed, illustrating the drug has the potential to impair driving performance, especially in sensitive subjects. Terfenadine, loratadine, levocetirizine, desloratadine, ebastine, bilastine fexofenadine and rupatadine showed no driving impairment in the standard driving test after acute administration of their recommended dose. Several studies examined subchronic effects of antihistamines on driving performance. After 4 days of daily treatment significant driving impairment was found for emedastine (2 and 4 mg bid), diphenhydramine (50 mg), clemastine (2 mg bid), triprolidine (5 mg bid), after 5 days of ebastine (30 mg), and after 8 days of hydroxyzine (50 mg). Mixed results were found for cetirizine (10 mg), terfenadine (120 mg) and loratadine (20 mg). No significant differences from placebo were observed after 4 days of subchronic treatment with triprolidine (10 mg), levocetirizine (5 mg), fexofenadine ...