The use of addictive substances by adolescents is a major public health concern; however, rural versus urban variations are poorly understood. The purpose of the current study was to examine rural-urban differences in the prevalence of recent use of 11 substances in grades 6 through 12 in a statewide sample of students from the Georgia Student Health Survey II (N = 513,909). We found that rural-urban differences in substance use depend largely upon grade level, with rural middle school students demonstrating higher rates of alcohol, smoking tobacco, and chewing tobacco use, and urban high school students demonstrating higher rates of illicit drugs.