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Introduction: COVID-19 emerged as a global clinical threat following an outbreak in China in late 2019. Objectives: The aim of the current study was to assess the effect of hemoperfusion in COVID-19 patients with respiratory failure. Patients and Methods: In this prospective study, a total of 98 patients over the age of 18 with the positive COVID-19 polymerase chain reaction (PCR) test were investigated. The patients were divided into two groups; a control group consisting of 47 patients who did not receive hemoperfusion, and an exposed group consisting of 51 patients who met the criteria for hemoperfusion. Various parameters including complete blood cell counts, serum bilirubin, creatinine, C-reactive protein (CRP), and interleukin 6 (IL-6) levels were evaluated in all patients. Results: The results of our study revealed a statistically significant difference in intensive care unit (ICU) admission between the two groups. Hospitalization time (19.941±1.75 versus 14.615±1.39, P=0.021) and ICU time (14.98±1.30 versus 9.62±1.15; P=0.003) were significantly higher in patients who received hemoperfusion. Regarding the mortality rate, only 36.7% of the patients survived; however, there was no significant difference observed between the two groups (P=0.34). Conclusion: In conclusion, the findings of our study indicate that hemoperfusion in COVID-19 patients with respiratory failure led to a significant increase in hospital stay and ICU stay compared to those without hemoperfusion. Further research is needed to determine the optimal timing and frequency of hemoperfusion to improve treatment outcomes in COVID-19 patients with respiratory failure.