BACKGROUND In the United States, rural areas have reported an increase in overdose deaths secondary to nonmedical use of prescription opioids. Little is known about the differences in nonmedical use of prescription opioids among urban and rural adults. METHODS Using the 2008-2009 National Survey on Drug Use and Health, we examined the prevalence of nonmedical use of prescription opioids in urban and rural counties and determined bivariate and multivariate associations, stratified by county. We also compared type of opioids, stratified by county. RESULTS Among 75,964 respondents, the prevalence of nonmedical use of prescriptions opioids was similar among residents in urban and rural counties (4.7% vs. 4.3%, p=0.15). Urban and rural residents with severe psychological distress and nonmedical use of other prescription medications were more likely to report nonmedical use of opioids. Urban residents whose first use of illicit drugs was between the age of 18 and 25 and who reported alcohol use were more likely to report nonmedical use. Black and Hispanic urban residents were less likely to use prescription opioids nonmedically compared to white urban residents. Rural residents were more likely than urban residents to use acetaminophen with propoxyphene (61.1% vs. 55.8%, p=0.02), methadone (14.8% vs. 9.1%, p=0.003) and acetaminophen with codeine (3.5% vs. 1.9%, p=0.05). CONCLUSIONS Prevalence and risk factors related to nonmedical use of opioids are similar between urban and rural residents; however rural residents report propoxyphene, codeine, and methadone use more than their urban counterparts. Prevention and treatment interventions may need to be tailored for specific communities.