The current study assessed whether risk factors associated with vaping were distinct from risk factors associated with other substance use (e.g., alcohol, cannabis) during adolescence. Participants (N = 848, ages 10-16 years) completed a self-report survey to assess frequency and age of onset of substance use, risk perceptions of use, risk factors (depressive symptoms, sensation seeking, and parent-reported factors), and vape nicotine content. Groups were created to differentiate types of substance use, and frequency of substance use. Overall, adolescents who only vaped had lower depressive symptoms and indicated less nicotine vape use than adolescents who vaped and used other substances. Experimental vapers perceived other substances (but not vaping) as risky and endorsed vaping nicotine less often than regular vapers. Early initiation of vaping was not associated with polysubstance use. Taken together, our findings offer important implications for how vaping can be differentiated from other substance use during adolescence.