Human papillomavirus (HPV) infection and menopause entail a considerable impairment in health-related quality of life (HRQoL). The objective of the present study was to analyze the impact of the menopause status on HRQoL in women with HPV infection. A cross-sectional, nationwide, multicenter sample of women with HPV infection was conducted throughout clinics of gynecology representative of the Spanish population with regard to age, geographic density, and autonomous regions. Demographic and clinical characteristics and the specific HPV-QoL questionnaire score with its domains were compared according to reproductive status: premenopausal and peri-/postmenopausal. Correlation with other validated patient-reported outcomes measurements was also tested, including General Health Questionnaire-12 (GHQ-12), Female Sexual Function Index (FSFI), and Hospital Anxiety and Depression Scale (HADS). A sample of 1,016 noninstitutionalized women, aged 18-80 y, was recorded, 191 (18.8%) peri-/postmenopausal and 825 (81.2%) premenopausal. Total HPV-QoL scoring was significantly lower in peri-/postmenopausal (38.8, 95% CI [35.2-42.4]) compared to premenopausal (46.4, 95% CI [45.0-47.8]) women, and also in every domain of the scale (P < 0.05), except in social well-being and health domains, with a small effect size of 0.39. In women with sexual dysfunction according to FSFI, adjusted total scoring and domains sexuality, general well-being, and psychological well-being scored significantly higher in premenopause women (P < 0.01), although the magnitude of differences were of small to moderate size. HRQoL was impaired during menopause in women with HPV infection according to HPV-QoL questionnaire. The sexuality domain was the most differentiating dimension between these populations.