BACKGROUND: A growing body of evidence supports the safety of the human papillomavirus (HPV) vaccines. However, concerns about autonomic dysfunction syndromes and non-specific symptoms continue to linger. These conditions are not easily captured by traditional diagnostic classification schemes and call for innovative approaches to the study of vaccine safety which take more general measures of all-cause morbidity into account. METHODS: Taking advantage of the unique Danish registers, including regional registration of absence from school, we conducted a cohort study of 14 068 adolescent Danish girls attending 5th through 9th grade in public schools in the municipality of Copenhagen during 1 August 2013-23 January 2018. We obtained time-varying HPV vaccination status and demographic information from nationwide registers. Using Poisson regression with random effects, we estimated rate ratios (RRs) of absence due to illness, comparing HPV-vaccinated girls with unvaccinated girls with adjustment for grade, season, calendar period, demographic factors and random effects at the individual, class and school levels. RESULTS: Our study included 6 206 188 school days with 213 221 days of absence from school due to illness (absence rate, 3.4%). Comparing absence rates due to illness in HPV-vaccinated and unvaccinated girls yielded an adjusted RR of 1.00 (95% confidence interval [CI], 0.98-1.03). CONCLUSIONS: Our study provides an important and novel contribution to HPV vaccine safety. Using absence from school records, we were able to address important safety concerns without relying on medical diagnoses. We conclude that HPV vaccination does not increase the risk of morbidity in any manner that manifests as absence from school due to illness.