Objective: To evaluate the therapeutic use of plasma exchange in COVID-19 patients compared to controls. Methods: A case series of critically ill adult men and non-pregnant women, ≥18 years of age, with laboratory-confirmed COVID-19, was studied at the Royal Hospital, Oman, from April 17 to May 11, 2020. Therapeutic plasma exchange (TPE) was performed on patients admitted to the intensive care unit (ICU) with confirmed or imminent acute respiratory distress syndrome (ARDS) or severe pneumonia. The analysis was performed using univariate statistics. Results: A total of 31 COVID-19 patients were included with an overall mean age of 51 ± 15 years (range: 27–76 years); 90% (n = 28) were males, and 35% (n = 11) of the patients had TPE as a mode of treatment. The TPE group was associated with higher extubation rates than the non-TPE cohort (73% versus 20%; p = 0.018). Additionally, patients on TPE had a lower 14 days (0 versus 35%; p = 0.033) and 28 days (0 versus 35%; p = 0.033) post plasma exchange mortality compared to patients not on TPE. However, all-cause mortality was only marginally lower in the TPE group compared to the non-TPE group (9.1% versus 45%; p = 0.055; power = 66%). Laboratory and ventilatory parameters also improved post TPE (n = 11). Conclusions: The use of TPE in severe COVID-19 patients has been associated with improved outcomes, however, randomized controlled clinical trials are warranted to draw final, conclusive findings.