Background: Nonmedical use of prescription pain relievers is second only to marijuana use as the nation's most prevalent illicit drug problem and is a public health concern, with approximately over 26 million people initiating nonmedical use of prescription pain relievers since 2002. Data on geographic variation in the nonmedical use of prescription pain relievers (and other drugs) are important for developing targeted prevention and treatment programs. Method: Combined 2012–2014 National Survey on Drug Use and Health national, regional, state-level, and substate-level estimates of nonmedical use of prescription pain relievers among people aged 12 or older were analyzed. Results: Nationally, 11.3 million people aged 12 or older used prescription pain relievers nonmedically in the past year, corresponding to 4.31 percent of the adult population. Across the census regions, estimates of past year nonmedical use of prescription pain relievers were 4.78 percent in the West, 4.30 percent in the South, 4.21 percent in the Midwest, and 3.82 percent in the Northeast. Among states, estimates of past year nonmedical use of prescription pain relievers ranged from 3.41 percent in Minnesota to 5.31 percent in Oklahoma. Among the substate regions, estimates of past year nonmedical use of prescription pain relievers ranged from 5.89 percent in Colorado’s Region 1 to 2.95 percent in Florida’s Southern region (Circuits 11 and 16). Comparisons of combined 2010–2012 data with combined 2012–2014 data showed that past year nonmedical use of prescription pain relievers among people aged 12 or older decreased at the national level, within 3 census regions (Northeast, Midwest, and West), and in 13 states. Conclusion: Highlighting the percentage of people who use prescription pain relievers nonmedically at state and substate levels can help policymakers inform their assessments of substance abuse needs in their communities.