Abstract Sleep modulates the immune response and sleep loss can reduce the immunogenicity of certain vaccinations. Vice versa immune responses impact sleep. We aimed to investigate the influence of mental health and sleep quality on the immunogenicity of COVID-19 vaccinations and, conversely, of COVID-19 vaccinations on sleep quality.The prospective CoVacSer study monitored mental health, sleep quality, and Anti-SARS-CoV-2-Spike IgG titres in a cohort of 1,082 healthcare workers from the 29th of September 2021 to the 19th of December 2022. Questionnaires and blood samples were collected before, 14 days, and three months after the third COVID-19 vaccination. In 154 participants the assessments were also conducted before and 14 days after the fourth COVID-19 vaccination.Healthcare workers with psychiatric disorders had slightly lower Anti-SARS-CoV-2-Spike IgG levels before the third COVID-19 vaccination. However, this effect was mediated by higher median age and body mass index in this subgroup. Antibody titres following the third and fourth COVID-19 vaccination (‘booster vaccinations’) were not significantly different between subgroups with and without psychiatric disorders. Sleep quality did not affect the humoral immunogenicity of the COVID-19 vaccinations. Moreover, the COVID-19 vaccinations did not impact self-reported sleep quality.Our data suggests that in a working population neither mental health nor sleep quality relevantly impact the immunogenicity of COVID-19 vaccinations and that COVID-19 vaccinations are not a precipitating factor for insomnia. The findings from this large-scale real-life cohort study will inform clinical practice regarding the recommendation of COVID-19 booster vaccination for individuals with mental health and sleep problems.