Several risk and protective factors are influential in predicting who uses or abstains from illicit substances during the high school years. The 2014 national cohort data from the Monitoring the Future survey shows the demographics, psychosocial factors, and attitudes regarding substance use that predict abstention by twelfth-graders (versus those who report any lifetime use of any illicit drugs). Being older, having a higher rate of sensation-seeking behaviors, perceiving drugs as easy to obtain, and participation of some social activities were associated with a lower rate of abstention. In contrast, being optimistic, involvement in school activities, perceiving drug and alcohol use as high risk, believing their peers disapprove of substance use, and personally disapproving of substance use were associated with greater abstention from lifetime substance use. A similar model including negative attitudes and experiences (nonuse-related) with marijuana was associated with a greater likelihood to abstain from substances. We examine possible explanations and prevention implications of these findings and discuss the role of abstention in post-high school substance use risks.