OBJECTIVES: We evaluated the impact of Florida’s prescription drug monitoring program (PDMP) and pill mill law on high-risk prescribers. METHODS: We used IMS Health’s LRx Lifelink database between July 2010 and September 2012 in Florida (intervention state) and Georgia (control state). We selected Georgia because it had not implemented a pill mill or PDMP law during our analysis period and is located in the same geographic region as Florida.  The pre-intervention, intervention, and post-intervention periods were: July 2010-June 2011, July 2011-September 2011, and October 2011-September 2012. High-risk prescribers are those in the top 5^th percentile of opioid volume during four consecutive calendar quarters.  We applied comparative interrupted time series models to evaluate policy effects on clinical practice patterns and prescribers’ monthly prescribing measures. We included 38,465/18,566 prescribers who had prescribed at least one opioid in Florida/Georgia in the pre-intervention period. We also performed two secondary analyses that examined subsets of these prescribers. RESULTS: We identified 1,526 (4.0%) high-risk prescribers in Florida, accounting for 67%/40% of total opioid volume/prescriptions. Relative to their lower-risk counterparts, they wrote about sixteen times the number of monthly opioid prescriptions (79 vs. 5, p<0.01), and were more likely to have prescription-filling patients receive opioids (47% vs. 19%, p<0.01). Following policy implementation, Florida’s high-risk providers experienced large relative reductions in the number of opioid patients and opioid prescriptions (-536 patients/month, 95% confidence intervals [CI] -829 to -243; -847 prescriptions/month, CI -1498 to -197), morphine equivalent dose (-0.88 mg/month, CI -1.13 to -0.62), and total opioid volume (-3.88 kg/month, CI -5.14 to -2.62). Low-risk providers did not experience statistically significantly relative reductions, nor did policy implementation affect the rank order of high vs. low prescribers. CONCLUSIONS: High-risk prescribers are disproportionately responsive to state policies. However, opioids-prescribing remains highly concentrated among high-risk providers following policy implementation.