Vaccines are undeniably an important tool for controlling infectious disease outbreaks, and they are the most certain way to end the epidemic risk. This brief report describes the characteristics of coronavirus disease 2019 (COVID-19) deaths among breakthrough and unvaccinated cases hospitalized in Fars province in the south of Iran. This cross-sectional study was performed to compare breakthrough and unvaccinated death cases in Fars, Iran (February 2, to August 19, 2021). Among 444,728 fully vaccinated people, 60,800 breakthrough cases were detected. Thus, 501 died, of which 297 (297/501) cases were hospitalized and compared with the unvaccinated dead group. The median age for breakthrough and unvaccinated cases was estimated 79 and 65 y, respectively. All signs and symptoms of COVID-19 were more frequent in the unvaccinated group. Decreasing O2 saturation (less than 93%) happened more often in the unvaccinated group significantly. Unvaccinated dead patients had significantly shorter hospital stays. These patients received 66.63% Sinopharm, 0.67% Sputnik, 0.67% COVIran Barekat, and 31.99% AstraZeneca vaccines. None of them were health-care staff. Equitable access to safe and effective vaccines is critical to ending the COVID-19 pandemic. As vaccine uptake increases, we observed a decrease in mortality and protection from severe forms of the disease.