Background: With the emergence of the coronavirus disease 2019 (COVID-19) and inability of healthcare systems to control the disease, various therapeutic theories with controversial responses have been proposed. Plasmapheresis was administered as a medication.However, the knowledge of its efficacy and indications is inadequate. This study evaluated the use of plasmapheresis in critically ill patients with cancer. Methods: This randomized clinical trial was conducted on 86 patients with malignancies, including a control group (N=41) and an intervention group (N=45) with severe COVID-19 during 2020-21. Both groups were treated with routine medications for COVID-19 management according to national guidelines, and plasmapheresis was applied to the intervention group. C-reactive protein (CRP), D-dimer, ferritin, lactate dehydrogenase, hemoglobin, and white blood cell, polymorphonuclear, lymphocyte, and platelet levels were measured at admission and at the end of plasmapheresis. Other variables included neutrophil recovery, intensive care unit admission, intubation requirements, length of hospital stay, and hospitalization outcomes. Results: CRP (P ＜0.001), D-dimer (P ＜0.001), ferritin (P =0.039), and hemoglobin (P =0.006) levels were significantly different between the groups after the intervention. Neutrophil recovery was remarkably higher in the case than in the control group (P ＜0.001). However, plasmapheresis did not affect the length of hospital stay (P =0.076), which could have significantly increased survival rates (P ＜0.001). Conclusion Based on the study findings, plasmapheresis led to a significant improvement in laboratory markers and survival rate in patients with severe COVID-19. These findings reinforce the value of plasmapheresis in cancer patients as a critical population suffering from neutropenia and insufficient immune responses.