In rural Virginia, drug overdose deaths increased 300% from 1997 to 2003. Polydrug deaths predominate (57.9%) in this review of 893 medical examiner cases. Prescription opioids (74.0%), antidepressants (49.0%), and benzodiazepines (39.3%) were more prevalent than illicit drugs. Two-thirds of decedents were 35-54 years old; 37% were female. When compared to western Virginia metropolitan cases, polydrug abuse was more common, specific medication combinations were found, the death rate per population was higher, and fewer illicit drugs were detected. These rural prescription overdose deaths differ from urban illicit drug deaths, suggesting the need for different strategies in prevention, treatment, and intervention by clinicians and policymakers.