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Background: In the present study, we aimed to evaluate the effects of medroxyprogesterone on hospital short clinical outcomes and ABG parameters in patients with chronic obstructive pulmonary disease (COPD) exacerbation under treatments with noninvasive ventilation (NIV) treated with progesterone 15 mg in comparison with placebo. Materials and Methods: This is a double-blinded clinical trial that was performed in 2020–2021 in Isfahan, Iran, on 60 patients with COPD exacerbation that require NIV. All patients received short-acting beta-agonists, short-acting anticholinergics, systemic corticosteroids, and NIV. Patients in the intervention group received tablets of progesterone 15 mg, every 6 h for 5 days and the control group received a placebo; patients in both groups received routine clinical cares. We collected data regarding the days requiring NIV, hospitalization duration, intubation, intensive care unit (ICU) admission, and death. Furthermore, blood pH, PCO2, O2 saturation, dyspnea score, and NIV hours usage per day were evaluated at the time of admission, 3 and 5 days during admission. Results: Hospital short clinical outcomes were not differently distributed between the two groups (P > 0.05). Comparing two groups during hospitalization in terms of short clinical outcomes including duration hospitalization, using NIV per day, ICU admission rate, and need to intubation showed that they are comparable (P > 0.05). PH in both groups improved during follow-up (P < 0.001) and patients in intervention groups showed higher improvement (P = 0.006). Mean PCO2 decreased significantly in the intervention group (P < 0.001) but not in the control group (P = 0.198) and totally intervention showed significant improvement in PCO2 compared with the control group (P = 0.047). Although mean O2 saturation was increased in both groups during follow-up period (P < 0.001, for both groups), two groups showed comparable (P = 0.910). Mean NIV using (hours/day) was decreased significantly in the intervention group (P = 0.023); however, it was not significantly higher than that was seen in the control group (P = 0.706). The mean dyspnea score was decreased in both groups (P < 0.001), although a greater decrease was seen in the intervention group (P < 0.001). Conclusion: Administration of medroxyprogesterone in patients with COPD exacerbation that required NIV was associated with significant improvements in blood pH, PCO2, dyspnea, and daily duration of NIV using after 3 and 5 days following hospitalization. [ABSTRACT FROM AUTHOR]