Background Reactogenicity of coronavirus disease 2019 (COVID-19) vaccines can result in inability to work. The object of this study was to evaluate health care workers' sick leave after COVID-19 vaccination and to compare it with sick leave due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and quarantine leave. Methods A multicenter cross-sectional survey was conducted at Regensburg University Medical Center and 10 teaching hospitals in South-East Germany from July 28 to October 15, 2021. Results Of 2662 participants, 2309 (91.8%) were fully vaccinated without a history of SARS-CoV-2 infection. Sick leave after first/second vaccination occurred in 239 (10.4%) and 539 (23.3%) participants. In multivariable logistic regression, the adjusted odds ratio for sick leave after first/second vaccination compared with BNT162b2 was 2.26/3.72 for mRNA-1237 (95% CI, 1.28-4.01/1.99-6.96) and 27.82/0.48 for ChAdOx1-S (95% CI, 19.12-40.48/0.24-0.96). The actual median sick leave (interquartile range [IQR]) was 1 (0-2) day after any vaccination. Two hundred fifty-one participants (9.4%) reported a history of SARS-CoV-2 infection (median sick leave [IQR] 14 [10-21] days), 353 (13.3%) were quarantined at least once (median quarantine leave [IQR], 14 [10-14] days). Sick leave due to SARS-CoV-2 infection (4642 days) and quarantine leave (4710 days) accounted for 7.7 times more loss of workforce than actual sick leave after first and second vaccination (1216 days) in all fully vaccinated participants. Conclusions Sick leave after COVID-19 vaccination is frequent and is associated with the vaccine applied. COVID-19 vaccination should reduce the much higher proportion of loss of workforce due to SARS-CoV-2 infection and quarantine.