Recent epidemiological studies have reported an association between the ABO blood group and the acquisition, symptom severity, and mortality rate of coronavirus disease 2019 (COVID-19). However, the association between the ABO blood group antigens and the type and severity of COVID-19 vaccine-related adverse reactions has not been elucidated. We conducted a cross-sectional, questionnaire-based study in Saudi Arabia from February to April 2022. The study cohort included adults who had received or were willing to receive at least two doses of a COVID-19 vaccine of any type. We used Chi-square test to assess the association between the ABO blood groups and vaccine-related adverse reactions. values of <0.05 were considered significant. Of the 1180 participants, approximately half were aged 18-30 years old, 69.2% were female, and 41.6% reported their blood group as O. The most frequent COVID-19 vaccine-related adverse reactions were fatigue (65%), pain at the injection site (56%), and headache (45.9%). These adverse reactions demonstrated significant correlations with the education level ( = 0.003) and nationality ( = 0.018) of the participants following the first dose, with gender ( < 0.001) following the second dose, and with the general health status ( < 0.001) after all the doses. Remarkably, no correlation was observed between the severity of the vaccine-related adverse reactions and ABO blood groups. Our findings do not support a correlation between the severity of COVID-19 vaccine-related adverse reactions and the ABO blood groups of the vaccinees. The creation of a national database is necessary to account for population differences.