Rationale: Lorazepam, a benzodiazepine anxiolytic, may increase daytime sleepiness and impair psychomotor performance, which is hazardous for patients engaging in daily activities such as car driving. Given current prescription practice, information on the repeated dose effects is required. The 5-HT_2A/2C antagonist ritanserin was originally developed as a safer alternative to the benzodiazepines, yet having limited clinical efficacy. 5HT_2A/2C receptors have been implicated in regulating slow-wave sleep but little is known about their role in human performance. Objective: The present study investigated the subchronic effects of the benzodiazepine anxiolytic lorazepam and the 5-HT_2A/2C antagonist ritanserin on actual driving performance, objective and subjective sleepiness, and nocturnal slow wave sleep. Methods: Eighteen healthy volunteers were treated twice daily for 7 days with ritanserin 5 mg, lorazepam 1.5 mg or placebo. Treatments were administered according to a double-blind, cross-over design. Tests were performed on day 7 of each treatment week. Sleep EEG was recorded during the preceding night. Results: Lorazepam had a pronounced impairing effect on lateral position control and induced daytime sleepiness, while having no effect on other parameters. In contrast, ritanserin did not impair driving performance or affect objectively measured daytime sleepiness, while subjects reported to feel more alert during daytime. Moreover, consistent with its effects on 5-HT₂ receptors, ritanserin increased the amount of nocturnal slow wave sleep. There were no relationships between changes in slow wave sleep and performance parameters. Conclusions: Lorazepam administered for 7 consecutive days may be hazardous for patients who engage in driving activities. Antagonism of 5-HT_2A/2C receptors, as accomplished by ritanserin, increases slow wave sleep and is devoid of effects on objective sleepiness and driving behaviour. Whether this extends to other cognitive and psychomotor domains remains to be established.