Catestatin is a pleiotropic peptide with a wide range of immunomodulatory effects. Considering that patients with a severe COVID-19 infection have a major immunological dysregulation, the aim of this study was to evaluate catestatin levels in patients with COVID-19 treated in the intensive care unit (ICU) and to compare them between the fatal and non-fatal outcomes. The study included 152 patients with severe COVID-19, out of which 105 had a non-fatal outcome and 47 had a fatal outcome. Serum catestatin levels were estimated by an enzyme-linked immunosorbent assay in a commercially available diagnostic kit. The results show that catestatin levels were significantly lower in the fatal group compared to the non-fatal group (16.6 +/- 7.8 vs. 23.2 +/- 9.2 ng/mL; p < 0.001). Furthermore, there was a significant positive correlation between serum catestatin levels and vitamin D levels (r = 0.338; p < 0.001) while there was also a significant positive correlation between serum catestatin levels and growth differentiation factor-15 (GDF-15) levels (r = -0.345; p < 0.001). Furthermore, multivariate logistic regression showed that catestatin, GDF-15 and leukocyte count were significant predictors for COVID-19 survival. These findings imply that catestatin could be playing a major immunomodulatory role in the complex pathophysiology of the COVID-19 infection and that serum catestatin could also be a predictor of a poor COVID-19 outcome.