Treatment of chronic idiopathic urticaria (CIU) is challenging because of its unpredictable course and negative influence on the quality of life. New treatments are being developed, but antihistaminics remain the cornerstone of the therapeutic approach. The purpose of this study was to compare the efficacy and safety of relatively new drug rupatadine with the established drug desloratadine in patients suffering from CIU. This prospective, randomized, open, outdoor-based clinical study was conducted at Department of Dermatology, Rajiv Gandhi Institute of medical sciences, Kadapa from February, 2013 to March, 2013. A total of 56 patients of CIU were randomized either to rupatadine group (n= 28) or desloratadine group (n=28). The efficacy variables were change in the total symptoms score(TSS), aerius quality of life questionnaire(AEQLQ) total score, differential count of eosinophil(DC-E), absolute eosinophil count(AEC) and serum IgE level from baseline visit to end of the study visit (after 4 weeks). Along with these the incidence of adverse effects were compared using different statistical tools. After four weeks, in rupatadine group, TSS decreased by 22.5 %( vs 10.8% in desloratadine group); AEQLQ total score decreased by 31 %( vs 17.7% in desloratadine group); AEC was decreased by 36.2% (vs 15% in desloratadine group); and serum IgE decreased by 13.3 %( vs 5.9% in desloratadine group). All the values were statistically significant (p<0.05) compared to desloratadine group. The overall incidence of adverse drug reactions was also found to be less in the rupatadine group. An analysis of the results of all the parameters of safety and efficacy proves the superiority of rupatadine over desloratadine for CIU.