Purpose: This study aimed to investigate the rate of COVID-19 breakthrough infection and adverse events in medical students.Methods: Iranian medical students receiving two doses of COVID-19 vaccines were included in this retrospective cohort study. The medical team gathered the demographic characteristics, comorbidities, type of vaccine, adverse events following vaccination, and history of COVID-19 infection data through a phone interview. The frequency of adverse events and breakthrough infection was stratified by vaccine type (ChAdOx1-S, Gam-COVID-Vac, and BIBP-CorV).Results: A total of 3591 medical students enrolled in this study, of which 57.02% were females, with a mean age of 23.31 + 4.87. A PCR-confirmed and suspicious-for-COVID-19 breakthrough infection rate of 4.51% and 7.02% was detected, respectively. There was no significant relation between breakthrough infection and gender, BMI, blood groups, and comorbidities. However, there was a significant difference in breakthrough infection rate among different types of vaccines (P=0.001) and history of COVID-19 infection (P=0.001). A total of 16 participants were hospitalized for COVID-19 infection, and no severe infection or death was observed in the studied population.Conclusion: Vaccination prevented severe COVID-19 infection, although a high breakthrough infection rate was evident among Iran medical students during the Delta variant’s peak. Vaccine effectiveness may be fragile during emerging new variants and in high-exposure settings. Moreover, adverse events are rare, and the benefits of vaccination outweigh the side effects. However, many limitations challenged this study, and the results should be cautious.