We investigated the effect of therapeutic plasma exchange (TPE) on life-threatening COVID-19; presenting as acute respiratory distress syndrome (ARDS) plus multi-system organ failure and cytokine release syndrome (CRS).We prospectively enrolled ten consecutive adult intensive care unit (ICU) subjects [7 males; median age: 51 interquartile range (IQR): 45.1-55.9 years old] with life-threatening COVID-19 infection. All had ARDS [PaO2/FiO2 ratio: 110 (IQR): 95.5-135.5], septic shock, CRS and deteriorated within 24 h of ICU admission despite fluid resuscitation, antibiotics, hydroxychloroquine, ARDS-net and prone position mechanical ventilation. All received 5-7 TPE sessions (dosed as 1.0 to 1.5 plasma volumes).All of the following significantly normalized (p 0.05) following the TPE completion, when compared to baseline: Sequential Organ Function Assessment score, PaO2/FiO2 ratio, levels of lymphocytes, total bilirubin, lactate dehydrogenase, ferritin, C-reactive protein and interleukin-6. No adverse effects from TPE were observed. Acute kidney injury and pulmonary embolism were observed in 10% and 20% of patients, respectively. The duration of mechanical ventilation was 9 (IQR: 7 to 12) days, the ICU length of stay was 15 (IQR: 13.2 to 19.6) days and the mortality on day-28 was 10%.TPE demonstrates a potential survival benefit and low risk in life-threatening COVID-19, albeit in a small pilot study.