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Introduction: Nebulized budesonide has been long used in chronic obstructive pulmonary disease (COPD) exacerbation. This study aimed to compare the effectiveness of nebulized budesonide (NB) versus oral prednisolone (OP) in increasing peak expiratory flow rate (PEFR) of COPD patients in emergency department (ED). Methods: Patients with COPD exacerbation, referring to ED were enrolled in this randomized trial study. In the first group, NB 0.5 mg every 30 minutes till three doses, placebo tablet, and standard treatment was administered. In the second group, nebulized normal saline, OP tablet 50 mg, and standard treatment were administered. Patients’ demographic data, vital signs, PEFR, venous blood gas (VBG) analysis, disposition, and patient and physician satisfaction were all collected and compared between the two groups. Results: 43 patients in the NB group and 41 patients in the OP group were evaluated. The two groups had similar age (p=0.544) and gender (p=0.984) distribution, duration of illness (p=0.458), and baseline PEFR (p=0.400). 12 and 24 hours after treatment, significant increase in PEFR in the NB and OP groups were observed (p=0.032 and 0.008; respectively). The upward trend of PEFR in NB group was significantly better than that of OP group during 24 hours of treatment (p=0.005). Vital signs and VBG results showed no significant differences between the two groups during the studied time interval. Conclusion: NB, compared to OP, could more effectively increase PEFR and ameliorate disease severity of patients with COPD exacerbation at 12 and 24 hours after treatment in ED.