According to current guidelines, oral antihistamines are the first-line treatment for chronic spontaneous urticaria (CSU). Up-dosing antihistamines to 4-fold the licensed dose is recommended if control is not achieved. Such indications are based mainly on expert opinion. Objectives: To critically review and analyze clinical evidence on the efficacy and safety of higher-than-licensed dosage of second-generation oral antihistamines in the treatment of CSU. A systematic literature review was performed following a sensitive search strategy. All articles published in PubMed, EMBASE, and the Cochrane Library between 1961 and October 2018 were examined. Publications with CSU patients prescribed secondgeneration antihistamines in monotherapy compared with placebo, licensed dosages, and/or higher dosages were included. Articles were evaluated by peer reviewers. Quality was evaluated using the Jadad and Oxford scores. We identified 337 articles, of which 14 were included in the final evaluation (fexofenadine, 6; cetirizine, 2; levocetirizine and desloratadine, 1; levocetirizine, 1; rupatadine, 2; ebastine, 1; and bilastine, 1). Only 5 studies were placebo-controlled. The number of patients included ranged from 20 to 439. The observation lapse was ≤16 weeks. High fexofenadine doses produced a significant dosedependent response and controlled urticaria in most patients. Cetirizine, levocetirizine, rupatadine, and bilastine were more effective in up-dosing. The most frequent adverse events were headache and drowsiness. The low quality and heterogeneity of the articles reviewed made it impossible to reach robust conclusions and reveal the need for large-scale randomized clinical trials.