BACKGROUND: There is a significant global burden of herpes simplex virus (HSV) related genital ulcer disease yet little is known about its impact on quality of life. This systematic review aimed to identify studies that quantitatively evaluated the effect of genital herpes on various aspects of health-related quality of life. METHODS: Six databases were searched (MEDLINE, EMBASE, NHS Economic Evaluation Database, Health Technology Assessment, Database of Abstracts of Reviews of Effects, Web of Science Core Collection) for primary quality of life and economic evaluations of genital herpes from January 1, 2000 to January 7, 2021. Qualitative studies or those without primary data were excluded. Two authors independently extracted data from the publications. The study's registration number with PROSPERO was CRD42021239410. FINDINGS: We identified 26 relevant publications: 19 presented primary quality of life data, and seven were economic evaluations. The primary studies presented a range of condition-specific tools for describing the quality of life in individuals with genital herpes, but only one study used a direct valuation that could be used to generate utility weights. All economic evaluations of HSV infection were from high-income country settings. Most (6 of 7) focused on neonatal HSV infection with utilities adopted from studies prior to 2000. INTERPRETATION: The extant literature on genital herpes-related quality of life is limited and requires updating. We recommend future studies be conducted in geographic- and population- diverse settings, and use preference-based condition-specific or generic-instruments to better inform economic modelling.