SummarySleep modulates the immune response, and sleep loss can reduce vaccine immunogenicity; 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 1082 healthcare workers from 29 September 2021 to 19 December 2022. Questionnaires and blood samples were collected before, 14 days, and 3 months after the third COVID‐19 vaccination, as well as in 154 participants 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 vaccinations (“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 suggest that in a working population neither mental health nor sleep quality relevantly impact the immunogenicity of COVID‐19 vaccinations, and that COVID‐19 vaccinations do not cause a sustained deterioration of sleep, suggesting that they 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 vaccinations for individuals with mental health and sleep problems.