Background: Many treatments for COVID-19 are currently under studying, such as combination therapies with hydroxychloroquine plus antiviral drugs. In this study, we compared the efficacy and side effects of two types of combination therapy including atazanavir /ritonavir (ATV/r) or lopinavir /ritonavir (LPV/r) plus hydroxychloroquine among COVID-19 patients. Methods: In a non-randomized clinical trial, 108 eligible patients with moderate and severe form of COVID-19 were divided into two groups. Each group consisted of 54 patients. One group received ATV/r plus hydroxychloroquine and the other group received hydroxychloroquine plus LPV/r. Then, the two groups were evaluated and compared for clinical symptoms, recovery rates and complications of treatment regimens. Results: The findings of this research showed a significant increase in bilirubin in ATV/r receiving group compared to LPV/r receivers (p<0.001). there was also a significant increase in arrhythmias in the LPV/r group compared to ATV/r group during the treatment period (p=0.019). Other findings including length of hospital stay, outcome, and treatment complications were not statistically significant. Conclusions: There is not statistically significant difference between protease inhibitor drugs including ATV/r and LPV/r in the treatment of COVID-19 regarding to progress and clinical outcomes. However, some side effects such as hyperbilirubinemia and arrhythmia was significantly different by application of atazanavir or lopinavir.