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The objective of our study is to evaluate the association between Ohio’s April 2012 emergency physician guidelines aimed at reducing inappropriate opioid prescribing and the number and type of opioid prescriptions dispensed by emergency physicians.We used Ohio’s prescription drug monitoring program data from January 1, 2010, to December 31, 2014, and included the 5 most commonly prescribed opioids (hydrocodone, oxycodone, tramadol, codeine, and hydromorphone). The primary outcome was the monthly statewide prescription total of opioids written by emergency physicians in Ohio. We used an interrupted time series analysis to compare pre- and postguideline level and trend in number of opioid prescriptions dispensed by emergency physicians per month, number of prescriptions stratified by 5 commonly prescribed opioids, and number of prescriptions for greater than 3 days’ supply of opioids.Beginning in January 2010, the number of prescriptions dispensed by all emergency physicians in Ohio decreased by 0.3% per month (95% confidence interval [CI] –0.49% to –0.15%). The implementation of the guidelines in April 2012 was associated with a 12% reduction (95% CI –17.7% to –6.3%) in the level of statewide total prescriptions per month and an additional decline of 0.9% (95% CI –1.1% to –0.7%) in trend relative to the preguideline trend. The estimated effect of the guidelines on total monthly prescriptions greater than a 3-day supply was an 11.2% reduction in level (95% CI –18.8% to –3.6%) and an additional 0.9% (95% CI –1.3% to –0.5%) decline in trend per month after the guidelines. Guidelines were also associated with a reduction in prescribing for each of the 5 individual opioids, with various effect.In Ohio, emergency physician opioid prescribing guidelines were associated with a decrease in the quantity of opioid prescriptions written by emergency physicians. Although introduction of the guidelines occurred in parallel with other opioid-related interventions, our findings suggest an additional effect of the guidelines on prescribing behavior. Similar guidelines may have the potential to reduce opioid prescribing in other geographic areas and for other specialties as well.