INTRODUCTION: Coronavirus disease 2019 (COVID-19) has been a serious obstacle in front of public health. Interferon-beta 1a (IFN-beta 1a) has been used to treat patients with COVID-19. We aimed to compare the effectiveness of high-dose IFN-beta 1a compared to low dose IFN-beta 1a in severe COVID-19 cases. METHODS: In this randomized, controlled, and clinical trial, eligible patients with confirmed SARS-CoV-2 infections were randomly assigned to receive one of the two following therapeutic regimens: The intervention group was treated with high-dose IFN-beta 1a (Recigen) (Subcutaneous injections of 88 mug (24 million IU) on days 1, 3, 6) + lopinavir /ritonavir (Kaletra) (400 mg/100 mg twice a day for 10 days, orally) and the control group was treated with low-dose IFN-beta 1a (Recigen) (Subcutaneous injections of 44 mug (12 million IU) on days 1, 3, 6) + lopinavir /ritonavir (Kaletra) (400 mg/100 mg twice a day for 10 days, orally). RESULT: A total of 168 COVID- 19 confirmed patients underwent randomization; 83 were assigned to the intervention group and 85 were assigned to the control group. Median Time To Clinical Improvement (TTIC) for cases treated with low-dose IFN-beta1a was shorter than that for cases treated with high-dose IFN-beta1a (6 vs 10 days; P = 0.018). The mortality rates in intervention and control group were 41% and 36.5%, respectively. CONCLUSION: The use of high-dose IFN-beta 1a did not improve TTCI in hospitalized patients with moderate to severe COVID-19. Also, it did not have any significant effect on mortality reduction compared with treating with low-dose IFN-beta 1a. TRIAL REGISTRATION: This trial has been registered as ClinicalTrials.gov, NCT04521400.