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Objectives: Genital lichen sclerosus (LS) is a chronic mucocutaneous disorder causing considerable discomfort. Despite this, comprehensive comparison of LS impacts on quality of life (QoL), particularly on men's health or relative to other dermatological conditions like pemphigus, are sparse. This research aims to discern the effects of LS on sexual functionality and overall QoL, benchmarking against pemphigus patients and healthy controls. The study's intent is to broaden the understanding of sexual dysfunction, satisfaction, and psychological distress attributable to LS., Materials and Methods: From March 2021 to September 2023, this observational multicenter study at the affiliated university hospitals involved 176 individuals, 120 females and 56 males, with LS, pemphigus, or as controls. Questionnaires employed were the Female Sexual Function Index or the International Index of Erectile Function depending upon subject's gender, the General Health Questionnaire-12, the Clinical Lichen Sclerosus Score, and Pemphigus Disease Area Index. Differences in QoL were analyzed using either the Fisher exact test or the Mann-Whitney U test, and the correlation between Clinical Lichen Sclerosus Score sexual QoL using Spearman's coefficient., Results: LS patients faced more sexual health challenges than pemphigus patients and healthy people. Women with LS had difficulties with lubrication and pain, men had less satisfaction during intercourse, and all had increased psychological distress, although less than those with pemphigus. A strong link between LS severity and worse sexual QoL, especially for women, was identified., Conclusions: LS significantly affects sexual function and psychological well-being, both for men and women, reaffirming the need for comprehensive management., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP.)