Background: The recently discovered instrumental role of CK2 in the SARS-Cov2 infection has pointed out this protein kinase as a promising therapeutic target in Covid-19 disease. Accordingly, anti-SARS-Cov2 activity has been reported by CK2 inhibitors in vitro, however any anti-CK2 clinical approach has been assessed in Covid-19 patients so far. Here, we investigated the putative clinical benefit of CIGB-325, an anti-CK2 peptide previously used in cancer patients, which was added to the standard-of-care to treat Covid-19. Methods: A monocentric, randomized standard-of-care controlled trial of intravenous CIGB-325 in adults hospitalized with Covid-19. Twenty patients were randomly assigned to receive CIGB-300 (2.5 mg/kg/day during 5-consecutive days) plus standard-of-care (10 patients) or standard-of-care (10 patients). Primary outcomes were time to viral clearance defined as the time (in days) to have nasopharyngeal SARS-Cov2 negative PCR and clinical response. This trial is registered with https://rpcec.sld.cu/trials/RPCEC00000317-En (Code: IG/CIGB300I/CV/2001). Results: Most of the patients had initial positive by chest-computed tomography (CT). CIGB-325 treatment reduced both number of pulmonary lesions and lesion's extent compared to control group in seven days. Taking into account the Covid-19 chest-CT abnormalities, CIGB-325 was also superior to control as well as in terms of proportion of patients with such clinical benefit. Improvement of clinical status was experienced in 50% of patients in the CIGB-325 group and 25% in control. Accordingly, systemic levels of CPK, LDH and CRP were lowered at day 7 by treating with this anti-CK2 peptide. Both therapeutic regimens were similar respect to SARS-Cov2 clearance in nasopharynx swabs over the time. Conclusion: Our study revealed that consecutive-5 day regimen of intravenous CIGB-325 at 2.5 mg/kg quickly improved the chest-CT outcomes over standard-of-care. This is the first report describing signs of clinical benefit of an anti-CK2 approach in Covid-19.