IntroductionPrimary hyperhidrosis (PHH) is a chronic condition characterized by excessive sweating. Several topical anticholinergic agents have been developed, but the evidence for the efficacy and tolerability of changing medication pathways of anticholinergics for PHH is limited.Methods and analysisPubMed, the Cochrane Library, Embase, the Web of Science, and the Cochrane Central Register of Controlled Trials will be searched from inception to March 2022 for studies that may be eligible for inclusion. Randomized controlled trials (RCTs) of PHH treated by topical anticholinergic drugs will be included. The primary outcomes include severity of hyperhidrosis measured quantitatively, the Hyperhidrosis Disease Severity Scale (HDSS) score or the proportion of subjects with a minimum 2-grade improvement from baseline in HDSS, the Hyperhidrosis Disease Severity Measure-Axillary (HDSM-Ax) score and Dermatology Life Quality Index (DLQI). The secondary outcomes focused on safety and tolerability. Study selection, data extraction and assessment of risk of bias will be performed by two investigators independently. Data synthesis will be performed with RevMan 5.4 software.Ethics and disseminationEthical approval will not be needed in this review due to no data are involved in patient’s information and privacy. The results will be published and diffused in a peer-reviewed journal or relative conferences.Strengths and limitations of this studyThis systematic review will be the first to evaluate the efficacy and safety of topical anticholinergic agents in the treatment of PHH.Different inclusion criteria between studies and different skin sites where drugs applied may lead to clinical heterogeneity, which will be explored in the subgroup analysis.This study will also focus on evaluating systemic and topical safety and tolerability of topical application of anticholinergics.