Background: Allergen immunotherapy (AIT)-associated adverse events are a major concern for safety and efficacy of AIT. Presently, there is no consensus to whether antihistamine premedication could improve such conditions. Objective: To identify the superiority of antihistamine pretreatment in AIT. Methods: A comprehensive literature search for randomized controlled trials reporting the effects of antihistamine premedication on safety and efficacy of AIT was performed in MEDLINE, Embase, and Cochrane Library databases. Safety was evaluated according to the number of patients reporting systemic adverse reactions (SARs, the primary outcome) and efficacy according to the number of patients achieving target maintenance dose (TMD) and sustained unresponsiveness to allergen. Results: A total of 11 randomized controlled trials (including 609 patients) satisfied the inclusion criteria for the meta-analysis. All premedication protocols were temporary. Pooled analysis revealed that compared with control patients, significantly fewer antihistamine-pretreated patients reported total and moderate-to-severe SARs (odds ratio [OR], 0.36; 95% confidence interval [CI], 0.23-0.56; P<.05 and OR, 0.20; 95% CI, 0.06-0.74; P<.05, respectively) and total and moderate-to-severe SAR episodes (OR, 0.42; 95% CI, 0.34-0.53; P<.05 and OR, 0.09; 95% CI, 0.01-0.50; P<.05, respectively). Similarly, antihistamine pretreatment significantly increased the number of patients achieving TMD (OR, 2.94; 95% CI, 1.72-5.03; P<.05), but not sustained unresponsiveness (OR, 1.65; 95% CI, 0.77-3.54; P = 0.2), compared with the control group. Subgroup analysis according to different allergens and dose-escalating approaches also displayed superiority of antihistamine pretreatment than control. Conclusion: Antihistamine premedication can markedly improve safety and efficacy of AIT by reducing frequency and severity of SAR and increasing TMD. (C) 2021 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc.