Objectives: The treatment of COVID-19 infection remains a challenge because till now, there is no approved therapy for it. This study aimed to estimate the difference in the therapeutic efficacy and safety between remdesivir as monotherapy and its use in combination with lopinavir/ritonavir provided with standard supportive care. Methods: This is a prospective randomized cohort study included 1043 adult patients with confirmed moderate and severe COVID-19 infection. Treatment of all patients followed Egyptian Ministry of Health COVID-19 protocol as the first group received IV remdesivir 200 mg on day 1, followed by 100 mg once daily, for 5 days while the second group received lopinavir/ritonavir 400/100 mg twice daily, for 5 days with the same remdesivir regimen in the first group. All laboratory and clinical parameters were assessed before and after treatment duration. Results: There was no significant difference related to improvement parameters such as laboratory data and improvement time between the two groups. On the other hand, hepatotoxicity of the second group (combination) was significantly higher compared with that of the first one. The elevation on liver enzymes was affected by the severity of the disease, the severe cases showed a high enzyme elevation rate. Conclusion: Remdesivir as monotherapy and its use in combination with lopinavir/ritonavir is effective in the management of moderate COVID 19 subjects than severe cases. The combination of remdesivir with lopinavir/ritonavir is not recommended due to the increased hepatotoxicity effect.