To properly assess an association between vaccines and specific adverse events requires a comparison between the observed and background rates; however, studies in South Korea are currently limited. Therefore, in this study, we estimated the background incidence of anaphylaxis, myocarditis, pericarditis, Guillain-Barré syndrome (GBS), and mortality in South Korea. A retrospective cohort study was conducted using the National Sample Cohort (NSC) data. Using NSC, the background incidence rate was estimated by dividing the number of episodes during 2009-2019 by the total population by year and then multiplying by 100,000. Using Statistics Korea data, the background mortality rate was estimated by dividing the number of deaths, during 2009-2019 by the standard population for that year and then multiplying by 100,000. Using background mortality rates, we predicted mortality rates for 2021 using autoregressive integrated moving average models. Further, the expected mortality rates were compared with observed mortality rates. The age-adjusted incidence rate (AIR) of anaphylaxis increased from 4.28 to 22.90 cases per 100,000 population (p = 0.003); myocarditis showed no significant increase, changing from 0.56 to 1.26 cases per 100,000 population (p = 0.276); pericarditis increased from 0.94 to 1.88 cases per 100,000 population (p = 0.005); and GBS increased from 0.78 to 1.21 cases per 100,000 population (p = 0.013). The age-adjusted mortality rate decreased from 645.24 to 475.70 deaths per 100,000 population (p <0.001). The 2021 observed/expected mortality rates for overall (ratio: 1.08, 95% confidence interval [CI]: 1.07-1.08), men (ratio: 1.07, 95% CI: 1.07-1.08), and women (ratio: 1.08, 95% CI: 1.07-1.09), were all significantly higher. When stratified by age group, those aged ≥80 (ratio: 1.16, 95% CI: 1.15-1.17), 60-69 (ratio: 1.11, 95% CI: 1.10-1.13), and 20-29 years old (ratio: 1.07, 95% CI: 1.02-1.13) were also significantly higher. Through the estimation of background rates related to anaphylaxis, myocarditis, pericarditis, GBS, and mortality, we established a reference point for evaluating the potential excess occurrence of adverse events following COVID-19 vaccination. This reference point serves as substantive evidence supporting the safety profile of COVID-19 vaccines.