Introduction: Though there is currently no approved treatment for COVID-19, potential medications include lopinavir and doxycycline. Lopinavir is a broad-spectrum protease inhibitor successfully used during the SARS outbreak. Doxycycline is an antibiotic with immunomodulatory effects, which successfully treats dengue hemorrhagic fever. Comparing lopinavir combined with doxycycline with other commonly implemented COVID-19 treatment regimens is of medical significance. Methods: We conducted a retrospective study comparing two cohorts. One cohort strictly adhered to a treatment protocol of lopinavir combined with doxycycline (Lop/Dox), while the other cohort (Others) applied protocols based on combinations of favipiravir, hydroxychloroquine, and azithromycin. The outcomes evaluated were death from coronavirus and intubation. Results: During the study period, 161 and 114 patients were followed in the Lop/Dox cohort and the Others cohort, respectively. The Lop/Dox cohort was older and had lower O2 saturation at admission. The proportion of patients needing intubation did not differ between the cohorts (Lop/Dox, 15∙5%; Others, 16∙7%). The overall fatality rate likewise did not differ (12∙4%) in Lop/Dox and 8∙7% in the Others cohort). Older age and elapsed time between the onset of symptoms and hospitalization, O2 saturation at admission, and the lymphocyte to white blood cell ratio were independent risk factors for poor outcomes of the illness. Conclusion: This study showed that lopinavir plus doxycycline therapy is an effective treatment amongst moderate to severe COVID-19 patients.