Introduction. Comirnaty® is an mRNA vaccine against COVID-19 which has been administered to millions of people since the end of 2020. Our aim was to study epidemiological and clinical factors influencing reactogenicity and functional limitation after the first two doses of the vaccine in health care workers (HCWs). Material and methods. Prospective post-authorization cohort study to monitor safety and effectiveness of the vaccine. Results. Local side effects were mild and presented both with first and second dose of Comirnaty. Systemic side effects were more frequent after 2nd dose. Nevertheless, previous SARS-CoV-2 infection was associated with systemic effects after the first dose of the vaccine (OR ranging from 2 to 6). No severe adverse effects were reported. According to multivariate analysis, the degree of self-reported functional limitation after the first dose increased with age, female sex, previous COVID-19 contact, previous SARS-CoV-2 infection, and Charlson Comorbidity Index (CCI). After the second dose, the degree of functional limitation observed was lower in those with previous SARS-CoV-2 infection, and it was positively associated to the degree of functional limitation after the first dose. Conclusion. Systemic adverse effects were more frequent after the second dose of Comirnaty. Previous SARS-CoV-2 infection was associated with systemic effects after the first dose. Age, female sex, previous COVID-19, previous isolation due to COVID-19 contact, and CCI showed to be independent predictors of the degree of functional limitation after the 1st dose of Comirnaty®. After the 2nd dose, the degree of functional limitation was lower in those who previously had SARS-CoV-2 infection.