Abstract Background Safe vaccination worldwide is critical for eliminating the COVID-19 pandemic elimination. We aimed to evaluate adverse reactions to vaccination using a web-based questionnaire and to examine the risk factors for the occurrence of immunisation stress-related response (ISRR). Methods We conducted a questionnaire survey using Google Form® among employees of St. Marianna University Hospital who had received the COVID-19 vaccine between April 2021 and May 2021, 1 week after the first and second vaccinations. We developed and used a questionnaire to identify individuals with ISRR, according to the World Health Organization diagnostic criteria. A generalised linear mixed model was constructed with ISRR onset as the dependent variable, subjects as the random factor, and each parameter as a fixed factor. A multivariate model was constructed using the forced imputation method with factors that were significant in the univariate analysis. Results We enrolled 2,073 and 1,856 respondents in the first and second questionnaire surveys, respectively. Fifty-five and 33 ISRR cases were identified in the first and second vaccinations, respectively. In the univariate analysis, strong pre-vaccination anxiety (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.30–4.12, p=0·004) and history of allergy (OR, 1.6; 95% CI, 1.14–2.24, p=0·007) were significant risk factors. Multivariate analysis also showed that strong pre-vaccination anxiety (OR, 2.1; 95% CI, 1.15–3.80, p=0.016) and history of allergy (OR, 1.5; 95% CI, 1.09–2.15, p=0.014) were significant risk factors. Conclusions Confirmation of allergy prior to vaccination and subsequent action are essential for addressing ISRR.