Background: Overuse and misuse of prescription opioids have become significant public health burdens in the United States. About 11.5 million people are estimated to have misused prescription opioids for nonmedical purposes in 2016. This has led to a significant number of drug overdose deaths in the United States. Previous studies have examined spatiotemporal clusters of opioid misuse, but they have been restricted to circular shaped regions. Objective: The goal of this study was to identify spatiotemporal hot spots of opioid users and opioid prescription claims using Medicare data. Methods: We examined spatiotemporal clusters with significantly higher number of beneficiaries and rate of prescriptions for opioids using Medicare payment data from the Centers for Medicare & Medicaid Services. We used network scan statistics to detect significant clusters with arbitrary shapes, the Kulldorff scan statistic to examine the significant clusters for each year (2013, 2014, and 2015) and an expectation-based version to examine the significant clusters relative to past years. Regression analysis was used to characterize the demographics of the counties that are a part of any significant cluster, and data mining techniques were used to discover the specialties of the anomalous providers. Results: We examined anomalous spatial clusters with respect to opioid prescription claims and beneficiary counts and found some common patterns across states: the counties in the most anomalous clusters were fairly stable in 2014 and 2015, but they have shrunk from 2013. In Virginia, a higher percentage of African Americans in a county lower the odds of the county being anomalous in terms of opioid beneficiary counts to about 0.96 in 2015. For opioid prescription claim counts, the odds were 0.92. This pattern was consistent across the 3 states and across the 3 years. A higher number of people in the county with access to Medicaid increased the odds of the county being in the anomalous cluster to 1.16 in both types of counts in Virginia. A higher number of people with access to direct purchase of insurance plans decreased the odds of a county being in an anomalous cluster to 0.85. The expectation-based scan statistic, which captures change over time, revealed different clusters than the Kulldorff statistic. Providers with an unusually high number of opioid beneficiaries and opioid claims include specialties such as physician?s assistant, nurse practitioner, and family practice. Conclusions: Our analysis of the Medicare claims data provides characteristics of the counties and provider specialties that have higher odds of being anomalous. The empirical analysis identifies highly refined spatial hot spots that are likely to encounter prescription opioid misuse and overdose. The methodology is generic and can be applied to monitor providers and their prescription behaviors in regions that are at a high risk of abuse.