BackgroundCoronavirus disease 2019 (COVID-19) is an infectious disease that shortly progressed into an unprecedented pandemic spreading all over the world and causing millions of deaths. Many new COVID-19-specific therapies were suggested for the treatment of the patients at increased risk of progression to severe disease, especially those who were unvaccinated and those with a likely inadequate vaccine response. One of the preferred therapies in this setting is Paxlovid, a combination of the oral protease inhibitors nirmatrelvir and ritonavir. Paxlovid was authorized by the Saudi Ministry of Health for the treatment of mild to moderate COVID-19. This study aimed to report the effects of Paxlovid on the mortality of the COVID-19 patients at Dammam Medical Complex (DMC) and Qatif Complex Hospital (QCH), two hospitals in the Eastern Provence of Saudi Arabia, and compare the results with the international data.MethodsThe study was a retrospective study that included all the COVID-19 patients who were treated with Paxlovid at DMC and QCH between January and December 2022. Those patients were compared with control COVID-19 patients who did not receive Paxlovid. The patients were included irrespective of their COVID-19 vaccination status. All the patients were managed according to the Saudi Ministry of Health guidelines. They were followed up through the infectious disease virtual clinics and were monitored for ICU admissions and death of any cause for three months following their COVID-19 infections.ResultsA total of 92 COVID-19 patients were included. The patients consisted of 47 male and 45 female patients (51.09% and 48.91%, respectively). The mean ± standard deviation for the patients' age was 55.58±19.25 years. Twenty-eight patients were given Paxlovid (30.43%). Eighteen patients (19.57%) died. The use of Paxlovid was associated with lower ICU admissions (0.0% vs. 18.75%, P value <0.05) and with lower deaths (3.57% vs 26.56%, P value <0.05) but the Paxlovid group included less immunocompromised patients (7.14% vs. 60.94%, P value <0.001), cancer patients (0.0% vs. 42.19%, P value <0.001), and chronic kidney disease patients (7.14% vs. 29.69%, P value <0.05) than the control group.ConclusionThis study suggests that Paxlovid is highly effective in reducing the risk of severe COVID-19 or mortality. However, larger studies with better qualities are needed for a full assessment of the role of Paxlovid in COVID-19 management in Saudi Arabia.