Genital human papillomavirus (HPV) infections and associated precancerous lesions decrease health-related quality of life (HRQoL). Since HPV vaccines protect effectively against these conditions we investigated the impact of HPV vaccination on HRQoL in young women five years after participation in a phase III HPV vaccination trial in comparison to an unvaccinated control cohort. A total of 4808 originally 16 to 17 year-old women had participated in the PATRICIA trial and received either bivalent HPV-16/18 vaccine or hepatitis A-virus (HAV) vaccine in 2004–2005. Unvaccinated adolescent women (n = 9602), from adjacent birth cohorts, consisted the control cohort. During 2009–2011, all participants received a questionnaire consisting of two generic HRQoL instruments (RAND36 and EQ VAS) and a disease-specific questionnaire (CECA10). We analysed responses of 1143 HPV-16/18 vaccinated-, 980 HAV vaccinated-, and 3753 unvaccinated young women. The unadjusted mean outcome measures of the different HRQoL estimates were similar in the three different responder cohorts. In conclusion, five-years after vaccination the HRQoL of HPV-16/18 vaccinated young women did not differ from that of HAV-vaccinated or unvaccinated controls representing the general population. This was somewhat unexpected, but the study should be repeated after a few years.