Background: First described in late 2019, coronavirus disease 2019 (COVID-19) has quickly become a major global public health problem. The causative agent of the disease was identified as the SARS-Co-2 virus, which at the beginning of the pandemic caused catastrophic consequences with poor outcomes, primarily due to the initial misunderstanding of the pathophysiological processes caused by the infection itself. The conclusion was gradually reached that the body's excessive immune response is the main cause of the most severe complications such as ARDS and failure of other vital organs. Catestatin is a pleotropic peptide and one of the products of chromogranin A, involved in many processes of the organism from the regulation of catecholamine secretion, immunoregulation, vasodilation, insulin resistance and even antimicrobial action. Due to the disturbed immunoregulation in patients with severe and critical form of COVID-19 and the participation of catestatin in immunomodulation processes, we decided to investigate the connection of catestatin with COVID-19. We also tried to find a link between vitamin D and GDF-15 with treatment outcomes of severe and critical forms of COVID-19 in the ICU. Methods: This study was conducted in the Intensive Care Unit for COVID patients of the Anesthesiology, Reanimation and Intensive Care Clinic of KBC Split in the period from September 2021 to February 2022. It included 152 patients with a severe and critical form of COVID-19 between the ages of 18 and 90 who, due to respiratory insufficiency, required mechanical respiratory support from admission to the ICU. All patients were sampled for laboratory tests after primary care. Part of the samples was analyzed daily, and part was centrifuged (20 minutes at 2000 revolutions/minute and at a temperature of 4 °C), aliquoted and stored in a refrigerator at -80 C and was used for subsequent analysis of serum concentrations of catestatin and GDF-15. All tests were performed according to the manufacturer's instructions. Results: Catestatin levels were significantly lower in the group of deceased compared to the group of surviving patients (p < 0.001). Serum vitamin D levels were significantly lower in the deceased group than in the survivor group (p < 0.001), while GDF-15 levels were significantly lower in the survivor group than in the deceased group (p < 0.001). In patients with severe and critical form of COVID-19, there was a significant positive correlation between serum catestatin levels and vitamin D levels (r = 0.338; p < 0.001) and a significant negative correlation between serum catestatin levels and GDF-15 levels (r = -0.345; p < 0.001). Multivariable logistic regression showed that catestatin levels were a significant negative predictor of COVID-19 mortality. GDF-15 levels (p < 0.001) and leukocyte count (p = 0.008) were significant positive predictors for COVID-19 mortality. Conclusion: The levels of catestatin and vitamin D were significantly lower in the group of deceased compared to the group of surviving patients with severe or critical form of COVID 19 treated in the ICU, while the levels of GDF-15 were decreased in the group of surviving patients. In patients with a severe and critical form of COVID-19, there was a significant positive correlation between catestatin and vitamin D, while in the same patients a negative correlation was found between catestatin and GDF-15. Catestatin proved to be a significant negative predictor for the fatal outcome of COVID-19, while GDF-15 and the level of leukocytes were significant positive predictors for the fatal outcome of COVID.