AbstractBackgroundRosacea is a chronic inflammatory disease mainly with skin or ocular manifestations. Topical calcineurin inhibitors, pimecrolimus and tacrolimus, can be used to treat rosacea. However, they can also induce rosacea‐like eruptions.AimsThis study systematically reviewed the double‐edged sword effects of pimecrolimus and tacrolimus on rosacea.MethodsFour databases were retrieved to search for articles on the effects of pimecrolimus and tacrolimus on rosacea, including Cochrane Library, Embase, PubMed, and Web of Science. Only English articles were included in the systematic review. Relevant data were collected, and the levels of evidence were evaluated.Results28 articles published between 2001 and 2016 were included. 11 articles were about pimecrolimus as the treatment of rosacea, 4 articles were about the pimecrolimus‐induced rosacea, 9 articles were about tacrolimus as the treatment of rosacea, and 4 articles were about tacrolimus‐induced rosacea. Participants for each study ranged from 1 to 200. Several types of outcome measurements were used for these publications.ConclusionsBoth pimecrolimus and tacrolimus might have double‐edged sword effects on rosacea. Pimecrolimus and tacrolimus could be effective for rosacea. However, both of them could also induce rosacea. Larger, randomized, controlled studies on pimecrolimus and tacrolimus as the treatment of rosacea and studies on the mechanisms of pimecrolimus and tacrolimus in treating or inducing rosacea are needed. This systematic review emphasized the double‐edged sword role of topical calcineurin inhibitors in rosacea, which may pave the way for future research.