This study characterizes the first clinical application of CIGB-258 in COVID-19 patients. CIGB-258 is an immunoregulatory peptide, derived from the cellular heat shock protein 60 (HSP60). Sixteen patients with COVID-19 in serious (31%) or critical (69%) conditions were included in this study. All critically ill patients recovered from the respiratory distress condition. Two of these patients had a fatal outcome due to nosocomial infections. The five seriously ill patients considerably improved. C-reactive protein (CRP) and interleukin-6 (IL-6) levels significantly decreased during treatment. CIGB-258 seems to be an effective and safe treatment option in COVID-19 patients under cytokine storm.