Lopinavir in combination with ritonavir are FDA approved HIV-1 protease inhibitors. Lopinavir was more potent in inhibiting HIV-1 than ritonavir in vitro but showed poor bioavailability in vivo. Ritonavir inhibits not only HIV-1 protease but also the host's cytochrome P450 3A4 enzyme that metabolizes lopinavir (Kempf et al., 1997). Lopinavir/ritonavir in combination prolongs bioavailability of lopinavir in vivo (Sham et al., 1998). Lopinavir but not ritonavir showed antiviral effect against SARS-CoV, MERS-CoV, and hCoV-229E in vitro, with mean EC50 ranged from 6.6 to 17.1 μM (de Wilde et al., 2014). Lopinavir/ritonavir in combination with ribavirin were used previously to treat SARS-CoV patients under a non-randomized clinical trial. Less SARS patients developed into ARDS or death after receiving the combination of lopinavir/ritonavir with ribavirin than historical controls who received ribavirin and corticosteroids (Chu et al., 2004). Efficacy of lopinavir/ritonavir with or without ribavirin is currently evaluated in SARS-CoV-2 patients under randomized control trials. In agreement with previous reports, we observed antiviral effect of lopinavir (EC50 at 26.1 μM) but not ritonavir against SARS-CoV-2 in vitro (Fig. 1B and Table 1). HIV-1 patients treated with 400 mg of lopinavir and 100 mg of ritonavir twice daily may reach the minimal lopinavir serum concentration at 9.4 μM (IQR 7.2–12.1 μM), which is below the EC50 against SARS-CoV-2 virus in vitro (Lopez-Cortes et al., 2013). Currently, lopinavir/ritonavir at 400mg/100 mg twice daily with or without ribavirin are part of the recommended treatment for managing COVID-19 patients in China (China National Health Commission, 2020). A recent randomized control trial reported no significant benefit of lopinavir-ritonavir in hospitalized SARS-CoV-2 patients than standard care, as the time to clinical improvement, mortality at 28 days, and viral loads at various time points were comparable between the two groups (Cao et al., 2020). Combinational therapy of lopinavir with the other effective compounds against SARS-CoV-2 virus may increase synergy and reduce the inhibitory concentration of lopinavir.