Objective: There are currently 39 FDA-approved metered-dose (MDI) or dry-powder inhalers (DPI) on the US market. Most are high cost with significantly more drug in the device than needed for a typical average length of stay in acute care hospitals, which leads to significant waste. The objective was to assess the financial impact and chronic obstructive pulmonary disease (COPD) outcomes of a comprehensive inhaler to nebulization protocol implemented in a large multi-state US health system. Methods: The retrospective study evaluated respiratory drug costs at 28 hospitals in the health system after a phased implementation of the automatic inhaler to nebulization protocol. Purchasing data was collected for all respiratory medications impacted by the protocol for the twelve months preceding as well as the two subsequent twelve-month periods following implementation at each facility. COPD length of stay (LOS) and 30 day readmissions were also reviewed. An attempt was made to evaluate the impact on respiratory therapy (RT) department workload. Results: Compared to pre-implementation, system-wide drug expenditures declined $1,561,011 (38.5%) and $1,646,411 (40.6%) in post-implementation year 1 (PY1) and post-implementation year 2 (PY2), respectively. COPD LOS and 30 day readmissions were not adversely affected and remained relatively stable in comparative periods. Objective impact on RT productivity and labor statistics was not ascertained due to complicated variables and multiple service lines. Conclusions: In an era of increased drug costs incurred by hospitals, a comprehensive inhaler to nebulization protocol significantly decreased costs without incurring any negative observed trends in COPD LOS or readmissions.