Inhaled epoprostenol (iEPO) has been utilized to improve oxygenation in mechanically ventilated subjects with severe hypoxemia, but the evidence for iEPO via high-flow nasal cannula (HFNC) is rare. Following approval by the institutional review board, this retrospective cohort study evaluated subjects who received iEPO via HFNC for more than 30 min to treat severe hypoxemia comorbid with pulmonary hypertension or right heart dysfunction between July 2015 and April 2018. A total of 11 subjects were enrolled in the study of whom 4 were male (36.4%), age 57.5 ± 22.1 years, and APACHE II score at ICU admission was 18.5 ± 5.7. Ten subjects had more than three chronic heart or lung comorbidities; seven of them used home oxygen. After inhaling epoprostenol, subjects’ SpO2/FIO2 ratio improved from 107.5 ± 26.3 to 125.5 ± 31.6 (p = 0.026) within 30–60 min. Five subjects (45.5%) had SpO2/FIO2 improvement >20%, which was considered as a positive response. Heart rate, blood pressure, and respiratory rate were not significantly different. Seven subjects did not require intubation, and seven subjects were discharged home. This retrospective study demonstrated the feasibility of iEPO via HFNC in improving oxygenation. Careful titration of flow while evaluating subjects’ response may help identify responders and avoid delaying other interventions. This study supports the need for a larger prospective randomized control trial to further evaluate the efficacy of iEPO via HFNC in improving outcomes.