Palm hyperhidrosis had a negative impact on quality of life. There was no FDA-approved treatment available. To assess the safety and efficacy of four different methods of applying glycopyrronium cloth to provide clinicians with guidance when treating palmar hyperhidrosis. This study compared application times of 15 minutes, 30 minutes without occlusion, and 30 minutes with occlusion. After 4 weeks of once-daily application, the primary endpoint was a decrease in the Hand Severity Score (HHS) mean’s mean. The cohort compiled data on safety, such as local skin reactions and other adverse events. Among the methods tested, 30 minutes without occlusion produced the greatest reduction in HHS while maintaining an acceptable safety profile. The most common adverse event was unilateral mydriasis, which was most likely caused by inadvertently introducing the study drug into the eye despite multiple warnings to subjects to avoid eye contact for treatment of axillary hyperhidrosis. Palmar hyperhidrosis could be successfully treated with glycopyrronium cloth. Occlusion for 30 minutes had the poorest response, owing to increased sweating, which caused dilution of the study drug.