This randomized, controlled, open-label trial evaluated the efficacy and safety of lopinavir–ritonavir in hospitalized adult patients with severe Covid-19. Patients with confirmed SARS-CoV-2 infection and an oxygen saturation of 94% or less while breathing ambient air or a PaO2/FiO2 ratio of less than 300 mm Hg were randomly assigned to receive either lopinavir–ritonavir (400 mg and 100 mg, respectively) twice daily for 14 days, plus standard care, or standard care alone. The primary endpoint was the time to clinical improvement, defined as improvement of two points on a seven-category ordinal scale or hospital discharge. A total of 199 patients were randomized, with 99 in the lopinavir–ritonavir group and 100 in the standard-care group. Treatment with lopinavir–ritonavir did not significantly reduce the time to clinical improvement compared to standard care (hazard ratio, 1.24; 95% CI, 0.90 to 1.72). Mortality at 28 days was similar between the two groups (19.2% vs. 25.0%). The median time to clinical improvement was slightly shorter in the lopinavir–ritonavir group (15 days vs. 16 days) in a modified intention-to-treat analysis. Gastrointestinal adverse events were more common in the lopinavir–ritonavir group, but serious adverse events were more common in the standard-care group. The trial concluded that lopinavir–ritonavir did not provide additional benefit beyond standard care in treating severe Covid-19.This randomized, controlled, open-label trial evaluated the efficacy and safety of lopinavir–ritonavir in hospitalized adult patients with severe Covid-19. Patients with confirmed SARS-CoV-2 infection and an oxygen saturation of 94% or less while breathing ambient air or a PaO2/FiO2 ratio of less than 300 mm Hg were randomly assigned to receive either lopinavir–ritonavir (400 mg and 100 mg, respectively) twice daily for 14 days, plus standard care, or standard care alone. The primary endpoint was the time to clinical improvement, defined as improvement of two points on a seven-category ordinal scale or hospital discharge. A total of 199 patients were randomized, with 99 in the lopinavir–ritonavir group and 100 in the standard-care group. Treatment with lopinavir–ritonavir did not significantly reduce the time to clinical improvement compared to standard care (hazard ratio, 1.24; 95% CI, 0.90 to 1.72). Mortality at 28 days was similar between the two groups (19.2% vs. 25.0%). The median time to clinical improvement was slightly shorter in the lopinavir–ritonavir group (15 days vs. 16 days) in a modified intention-to-treat analysis. Gastrointestinal adverse events were more common in the lopinavir–ritonavir group, but serious adverse events were more common in the standard-care group. The trial concluded that lopinavir–ritonavir did not provide additional benefit beyond standard care in treating severe Covid-19.