Background: The mortality rate of critically ill patients with coronavirus disease 2019 (COVID-19) was high. We aimed to assess the association between prolonged intermittent renal replacement therapy (PIRRT) and mortality in patients with COVID-19 undergoing invasive mechanical ventilation. Methods: This retrospective cohort study included all COVID-19 patients receiving invasive mechanical ventilation between February 12 and March 2, 2020. All patients were followed until death or March 28, and all survivors were followed for at least 30 days. Results: For 36 hospitalized COVID-19 patients receiving invasive mechanical ventilation, the mean age was 69.4 (+/- 10.8) years, and 30 patients (83.3%) were men. Twenty-two (61.1%) patients received PIRRT (PIRRT group), and 14 cases (38.9%) were managed with conventional strategy (non-PIRRT group). There were no differences in age, sex, comorbidities, complications, treatments, and most of the laboratory findings. During the median follow-up period of 9.5 (interquartile range 4.3-33.5) days, 13 of 22 (59.1%) patients in the PIRRT group and 11 of 14 (78.6%) patients in the non-PIRRT group died. Kaplan-Meier analysis demonstrated prolonged survival in patients in the PIRRT group compared with that in the non-PIRRT group (p = 0.042). The association between PIRRT and a reduced risk of mortality remained significant in 3 different models, with adjusted hazard ratios varying from 0.332 to 0.398. Increased IL-2 receptor, TNF-alpha, procalcitonin, prothrombin time, and NT-proBNP levels were significantly associated with an increased risk of mortality in patients with PIRRT. Conclusion: PIRRT may be beneficial for the treatment of COVID-19 patients with invasive mechanical ventilation. Further prospective multicenter studies with larger sample sizes are required.