Sustained vigilance is required by pilots and crew during flight; therefore, the use of antihistamines with sedating properties is widely prohibited. The purpose of this study was to determine the effects of desloratadine, a long-acting, nonsedating antihistamine, on healthy volunteers placed under conditions of simulated cabin pressure. Methods: In a double-blind crossover study, 21 subjects randomly received single doses of desloratadine 5 mg, diphenhydramine 50 mg (active control), and placebo on different days separated by washout periods of 7 d. On test days, predose levels of alertness and fatigue were determined, as were post-dose levels at 1, 2, 3, 5, and 6 h. Measurements included vigilance and tracking, a multi-attribute task battery, the Stanford Sleepiness Scale, and pulse oximetry. Results: Desloratadine had no detrimental effects on sleepiness or performance of tasks associated with flying ability. Conversely, diphenhydramine (active control) caused significantly more sleepiness than did the placebo [F (2,40) = 6.52, p < 0.01], as well as impaired performance (tracking performance p < 0.05 at 3 h post dose), and an increased percentage of omissions (p < 0.05 at 2 h post dose). Conclusion: A single dose of desloratadine 5 mg did not cause sleepiness and did not impair the performance of tasks associated with flying ability.