A randomized, controlled trial evaluated the effectiveness of lopinavir-ritonavir in adults hospitalized with severe Covid-19. The study included 199 patients with confirmed SARS-CoV-2 infection, randomly assigned to receive lopinavir-ritonavir (400 mg and 100 mg twice daily) plus standard care or standard care alone for 14 days. The primary endpoint was time to clinical improvement, defined as improvement on a seven-category ordinal scale or hospital discharge. The trial found no significant difference in time to clinical improvement between the two groups, with hazard ratios of 1.24 and 1.39 in intention-to-treat and modified intention-to-treat analyses, respectively. Mortality at 28 days was similar in both groups (19.2% vs. 25.0%). Viral RNA detection rates were similar in both groups at various time points. Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, while serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped in 13 patients (13.8%) due to adverse events. The study concluded that lopinavir-ritonavir did not provide additional benefit beyond standard care in hospitalized adults with severe Covid-19. Future trials may help confirm or exclude the possibility of a treatment benefit. The study was funded by the National Science and Technology on New Drug Creation and Development and the Chinese Clinical Trial Register. The authors note that the trial was not blinded, and the results should be interpreted with caution due to potential confounding factors. The study highlights the need for further research to assess the efficacy of lopinavir-ritonavir in treating SARS-CoV-2 infections.A randomized, controlled trial evaluated the effectiveness of lopinavir-ritonavir in adults hospitalized with severe Covid-19. The study included 199 patients with confirmed SARS-CoV-2 infection, randomly assigned to receive lopinavir-ritonavir (400 mg and 100 mg twice daily) plus standard care or standard care alone for 14 days. The primary endpoint was time to clinical improvement, defined as improvement on a seven-category ordinal scale or hospital discharge. The trial found no significant difference in time to clinical improvement between the two groups, with hazard ratios of 1.24 and 1.39 in intention-to-treat and modified intention-to-treat analyses, respectively. Mortality at 28 days was similar in both groups (19.2% vs. 25.0%). Viral RNA detection rates were similar in both groups at various time points. Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, while serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped in 13 patients (13.8%) due to adverse events. The study concluded that lopinavir-ritonavir did not provide additional benefit beyond standard care in hospitalized adults with severe Covid-19. Future trials may help confirm or exclude the possibility of a treatment benefit. The study was funded by the National Science and Technology on New Drug Creation and Development and the Chinese Clinical Trial Register. The authors note that the trial was not blinded, and the results should be interpreted with caution due to potential confounding factors. The study highlights the need for further research to assess the efficacy of lopinavir-ritonavir in treating SARS-CoV-2 infections.