Prior literature has reported on the concerning emergence of opioid overprescribing, yet there remains a lack of knowledge in understanding the cost of waste of this over-prescription and underconsumption of opioids. As such, further investigating the cost of waste of opioids following orthopedic surgery is of interest to patients, providers, and payors. In one of the largest private orthopedic practices in the United States, opioid prescribing and consumption patterns were tracked prior to, and after the implementation of, formal prescription guidelines. To (1) establish the cost of waste of unused opioids before the implementation of formal prescription guidelines and (2) examine how the cost of unused opioids may be reduced after implementation of formal internal prescription guidelines. Two separate phases (Phase I and Phase II) were implemented at different time intervals throughout a two-year period. Implementation of prescription guidelines occurred between Phases I and II, and data from Phase I (pre-implementation) was compared to that from Phase II (postimplementation). Data collection included type, dosage, quantity of opioids prescribed and consumed after elective outpatient procedures in ambulatory surgery centers, in addition to patient interviews/surveys within two weeks after surgery to measure consumption. From these data, the cost of waste was calculated by taking the total cost of prescribed opioids (sum of each prescription × Average Wholesale Price (AWP) minus 60%) per 1,000 patients, and subtracting the total cost of consumed opioids per 1,000 patients, calculated in a similar manner. Further analysis was performed to describe differences in the cost of waste of individual opioids between each of the phases. In Phase I, prior to implementation of formal internal prescription guidelines, there was a sizable cost of waste of unused opioids (per 1,000 patients, AWP minus 60%) of $11,299.51. The cost of waste in Phase II, after implementation of formal internal prescription guidelines, was $6,117.12, which was a significant decrease of 45.9% ($5,182.39) from Phase I ( < 0.001). Furthermore, both the average number of morphine equivalent units prescribed and consumed per patient decreased from Phase I to Phase II (294.6 vs 187.8, < 0.001; and 144.9 vs 96.0, < 0.001, respectively). Finally, in describing individual medications, there was a significant decrease in cost of waste (per 1,000 patients, AWP minus 60%) between Phases I and II for- Hydrocodone with APAP 5/525 mg (< 0.001), Oxycodone CR 10 mg (< 0.001), Morphine CR 15 mg (=0.001), and Tramadol 50 mg ( = 0.014). The results of this study suggest that there is a significant cost of waste associated with differences in prescribed versus consumed opioids following elective orthopedic surgery. This cost of waste was significantly reduced following the introduction and implementation of formal prescription guidelines. This study was funded internally by Revo Health and Twin Cities Orthopedics. Giveans reports consulting fees from Medtrak, Inc., and Superior Medical Experts. The other authors have nothing to disclose.