Objectives: To systematically review the effect and safety of epicutaneous immunotherapy (EPIT) for allergic diseases., Methods: We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, CQ VIP Database, Wanfang Data, and international trial register from their inception to July 29, 2019, without language restrictions, for randomized controlled trials (RCTs) that compared EPIT versus no EPIT for allergen-triggered allergic reactions. We assessed certainty of evidence by the GRADE approach., Results: Ten RCTs with 1,085 participants (aged from 10 months to 65 years) comparing EPIT with placebo for peanut, cow milk, or grass-pollen allergy met the eligibility criteria. A substantial benefit in terms of desensitization in EPIT group was more likely for peanut or cow milk protein allergy (risk ratio [RR] 2.34, 95% CI 1.69-3.23; I2 = 0%; high certainty evidence). EPIT increased local-treatment-related adverse events (L-TRAE; RR 1.56, 95% CI 1.03-2.36; I2 = 82%; moderate certainty evidence). But there were no significantly increased risk of any TRAEs (low certainty evidence) or systemic-TRAEs (S-TRAEs; very low certainty evidence) in EPIT group. The incidence rate of serious AEs, the use of rescue medications, and anaphylactic reactions stratified by organ systems including skin and mucosa, eyes and upper respiratory, lower respiratory, and gastrointestinal system in EPIT group were similar to placebo group. In subgroup analysis, desensitization of EPIT was significantly effective in peanut allergy (RR 2.29, 95% CI 1.64-3.21; I2 = 0%) and children <12 years (RR 2.85, 95% CI 1.92-4.24; I2 = 0%) with high certainty evidence. Only epicutaneous grass-pollen immunotherapy significantly increased the risk of S-TRAE (RR 4.65, 95% CI 1.10-19.64; I2 = 0%)., Conclusion: The systematic review suggests that EPIT might induce desensitization in peanut allergy and an increased risk of local AEs. These findings should be interpreted with caution owing to the limited study and heterogeneity. More data in the older (children ≥12 years and adults) and other allergic diseases are needed., (© 2019 S. Karger AG, Basel.)