Introduction: Antidepressant drugs vary in their effects on sleep, day-time sedation and performance. Up to now, no data are available for either escitalopram (ESCIT) or amitriptyline (AMI), measuring these by an objective test, such as the multiple sleep latency test (MSLT). Subjects and Methods: We therefore investigated the impact of a single evening dose of 10 mg ESCIT on polysomnographically recorded nocturnal sleep, day-time sleepiness and performance in comparison to 75 mg AMI and placebo (PLAC) in healthy male subjects. Results: Both antidepressants significantly suppressed REM sleep (p < 0.001). Although polysomnographically measured sleep continuity was impaired after ESCIT (p = 0.006), subjective estimates of sleep parameters did not differ. Periodic limb movements (PLMS) were increased after AMI (p < 0.001) but not after ESCIT. Processing speed and performance were enhanced after ESCIT compared with AMI (p = 0.011), but not with PLAC. Next-day alertness was significantly impaired by AMI (p = 0.012), but not by ESCIT. Mean day-time sleep onset latencies increased significantly after evening ESCIT (p < 0.001). In contrast, AMI led to a pronounced increase of day-time sleepiness (p = 0.007). Discussion: This study demonstrates that single evening doses of either AMI or ESCIT exhibit different effects on next-day vigilance and alertness in terms of a slightly stimulating effect of ESCIT and a significant reduction after AMI.