Background: Chronic idiopathic urticaria (CIU) has a major impact on patient well-being. Antihistamines are the first-line treatment for CIU; however, some cause sedation. Objective: Our purpose was to study the efficacy and safety of desloratadine, 5 mg, a new H₁-receptor antagonist, in patients with moderate to severe CIU. Methods: This study was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial of 6 weeks' duration. Results: Compared with placebo, desloratadine significantly improved the total CIU symptom score as well as pruritus, the number of hives, and the size of the largest hive. Overall therapeutic response and global CIU status improved significantly with desloratadine; interference with sleep was reduced and the performance of daily activities improved. Statistically and clinically significant improvements were seen within the first 24 hours of treatment and were sustained throughout the full duration of the study. The incidence of adverse events, including somnolence, was similar in the desloratadine and placebo groups. Conclusion: Desloratadine is a well-tolerated and effective treatment of CIU. (J Am Acad Dermatol 2003;48:535-41.)