Objective-This report describes regional differences in the specific drugs most frequently involved in drug overdose deaths in the United States in 2017. Methods-Data from the 2017 National Vital Statistics System-Mortality files were linked to electronic files containing literal text information from death certificates. Drug overdose deaths were identified using International Classification of Diseases, 10th Revision underlying cause-of-death codes X40-X44, X60-X64, X85, and Y10-Y14. Drug mentions were identified using established methods for searching the literal text from death certificates. Deaths were assigned to 1 of 10 U.S. Department of Health and Human Services (HHS) regions based on the decedent's state of residence. The number and age-adjusted death rate was determined for the 10 drugs most frequently involved in drug overdose deaths in 2017, both nationally and for each HHS region. Deaths involving more than one drug were counted in all relevant drug categories (i.e., the same death could be counted in more than one drug category). Results-Among drug overdose deaths in 2017 that mentioned at least 1 specific drug on the death certificate, the 10 drugs most frequently involved included fentanyl, heroin, cocaine, methamphetamine, alprazolam, oxycodone, morphine, methadone, hydrocodone, and diphenhydramine. Regionally, 6 drugs (alprazolam, cocaine, fentanyl, heroin, methadone, and oxycodone) were found among the 10 most frequently involved drugs in all 10 HHS regions, although the relative ranking varied by region. Age-adjusted rates of drug overdose deaths involving fentanyl or deaths involving cocaine were higher in the regions east of the Mississippi River, while age-adjusted rates for drug overdose deaths involving methamphetamine were higher in the West. The regional patterns observed did not change after adjustment for differences in the specificity of drug reporting. Conclusions-The drugs most frequently involved in drug overdose deaths in 2017 varied by HHS region. Understanding the regional differences can help inform local prevention and policy efforts.