In an effort to focus substance use prevention efforts in high schools, a recent study explored the relationship between first substance use initiation and lifetime substance use among high school seniors in the United States. By conducting a secondary data analysis using primary data published from the Monitoring the Future Study (specific report year not indicated), this study aimed to: 1) determine the first substance high school seniors initiated use of; 2) determine the order that they progressed through initiating alcohol, marijuana, and tobacco use; and 3) evaluate how the age at first substance use initiation impacted lifetime substance use. Secondary data analysis indicated that high school seniors (n=2385) reported alcohol as the most common substance used (only 30% had never used), as well as the first illicit substance initiated by the majority of respondents. In addition, the most common pattern reported for substance use initiation included trying alcohol, followed by marijuana and tobacco (n=644/2385). Lastly, statistical analyses suggested increased lifetime substance use when alcohol use was initiated in 6th, 7th, or 8th grade compared to initiation in 9th grade. Respondents that had never consumed alcohol by 12th grade reported the lowest lifetime use of illicit substances as well as the lowest frequency of substance use. Take Away: Although this report provides evidence for high schools to focus their prevention efforts on alcohol use, these findings can also extend to prevention efforts targeting first year students on college campuses. This study suggests preventing or decreasing alcohol use may also help reduce polysubstance use later in life.