Objectives: Healthcare facilities are high-risk sites for infection. This study analyzed the epidemiological characteristics of a coronavirus disease 2019 (COVID-19) outbreak in a tertiary hospital after COVID-19 vaccination had been introduced in Republic of Korea. Vaccine effectiveness (VE) and shared anti-infection strategies are also assessed.Methods: The risk levels for 4,074 contacts were evaluated. The epidemiological characteristics of confirmed cases were evaluated using the chi-square test. The “1 minus relative risk” method was used to determine VE in preventing infection, progression to severe disease, and death. In the largest affected area (the 8th floor), a separate relative risk analysis was conducted. A multivariate logistic regression analysis (with 95% confidence interval [CIs]) was used to identify transmission risk factors with a significance level <10% via the backward elimination method.Results: In total, 181 cases of COVID-19 were confirmed, with an attack rate of 4.4%. Of those cases, 12.7% progressed to severe disease, and 8.3% died. In the cohort isolation area on the 8th floor, where 79.0% of the confirmed cases occurred, the adjusted odds ratio was 6.55 (95% CI, 2.99–14.33) and 2.19 (95% CI, 1.24–3.88) for caregivers and the unvaccinated group, respectively. VE analysis revealed that 85.8% of the cases that progressed to severe disease and 78.6% of the deaths could be prevented by administering a second vaccine.Conclusion: Caregiver training for infection prevention and control is necessary to reduce infection risk. Vaccination is an important intervention to reduce the risk of progression to severe disease and death.