Background <p>COVID-19 patients frequently present with various comorbidities. Two developed antiviral medications, nirmatrelvir/ritonavir and molnupiravir, have been utilized in COVID-19 patients; but comparisons of the effectiveness between nirmatrelvir/ritonavir and molnupiravir in COVID-19 patients with different comorbidities remain unknown. This study aims to compare the effectiveness, including invasive ventilation and mortality, of nirmatrelvir/ritonavir and molnupiravir in the overall population and populations with various comorbidities in Taiwanese patients during the omicron BA.2 wave.</p> Methods <p>We retrospectively collected electronic medical records from the Taipei Medical University Clinical Research Database between January and December 2022 and conducted an analysis of adult patients diagnosed with SARS-CoV-2 infection. For data management, we performed propensity score matching to minimize the imbalance between two groups; the standardized mean difference &gt; 0.1 or a p value &lt; 0.05 considered statistically significant. Variables, which remained imbalanced after matching, were adjusted by cox regression model. To identify the risk associated with these variables, a Cox proportional hazards model were performed. Kaplan-Meier method was applied to estimate invasive ventilation and mortality, comparing survival curves between nirmatrelvir/ritonavir users and molnupiravir users.</p> Results <p>Our cohort was recruited from a database, including patients who receive nirmatrelvir/ritonavir or molnupiravir treatment. Out of a total of 35,617 patients, 968 patients received nirmatrelvir/ritonavir and 1198 patients received molnupiravir after matching. Patients with chronic liver disease or mental disease on nirmatrelvir/ritonavir had lower risks of intubation than those on molnupiravir. Overall, nirmatrelvir/ritonavir reduced mortality risk by 65% (adjusted hazard ratio (aHR): 0.35, 95% confidence interval (CI): 0.14–0.88, <i>p</i> = 0.026). For patients with diabetes mellitus (aHR: 0.29, 95% CI: 0.11–0.78, <i>p</i> = 0.014), with chronic kidney disease (aHR: 0.26, 95% CI: 0.10–0.68, <i>p</i> = 0.007), or aged over 65 years (aHR: 0.30, 95% CI: 0.13–0.70, <i>p</i> = 0.005), nirmatrelvir/ritonavir demonstrated superior efficacy in reducing mortality risk compared to molnupiravir.</p> Conclusions <p>Data revealed that both nirmatrelvir/ritonavir and molnupiravir demonstrated clinical benefits in treating COVID-19 patients in a real-world setting. Moreover, nirmatrelvir/ritonavir was associated with a lower risk of mortality in COVID-19 patients with specific circumstances.</p> Clinical trial <p>Clinical trial number is not applicable.</p>