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Purpose: To evaluate clinical outcomes and costs of inhaled corticosteroid (ICS) and systemic corticosteroid combination therapy versus systemic corticosteroid monotherapy for treatment of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Methods: Hospitalized patients aged 41 to 85 years old who received ≥40 mg/day of systemic prednisone equivalents between April 3, 2017 to July 31, 2017 and April 3, 2018 to July 31, 2018 with a primary discharge diagnosis of AECOPD. Two cohorts were identified: those who received >2 doses of ICS (combination therapy) and those who received ≤2 doses of ICS (monotherapy) while on systemic corticosteroid therapy. Primary outcomes were progression of respiratory support or ≥20% increase in daily dose of systemic corticosteroids. Secondary outcomes were hospital length of stay (LOS), COPD 30-day readmissions, in-hospital mortality, and nebulized budesonide costs. Results: One hundred twenty-eight patients met inclusion criteria. Daily corticosteroid dose increases were similar between the combination and monotherapy cohorts (4% vs. 5%, P = 0.76) as was progression in ventilatory support (12% vs. 8%, P = 0.53). In-hospital mortality (4% vs. 1%, P = 0.36) and COPD 30-day readmissions (16% vs. 9%, P = 0.22) were not significantly different, however, patients in the combination arm had longer lengths of stay (4.8 days vs. 3.9 days, P = 0.04). Total nebulized budesonide costs were $1857 with a mean of $37 per patient stay for combination therapy cohort. Conclusion: Outcomes showed no clinical difference between combination therapy and monotherapy. This study suggests monotherapy may be more cost-effective while providing similar outcomes for the treatment of hospitalized patients with AECOPD.