Objective: Electronic nicotine delivery system (ENDS) use on college campuses increased dramatically in recent years. Little is known about how ENDS use among college students relates to other substance use. Participants: Undergraduates (n = 3,917) at a mid-sized Midwestern public university in the United States. Methods: Cross-sectional survey data and latent class analysis of ENDS, cigarettes, alcohol, marijuana, and non-medical use of attention-deficit/hyperactivity disorder (ADHD) medication. Results: Over 95% of ENDS users fit into one of two classes comprising a minority of college students engaged in multiple and often problematic substance use behaviors. Only 4% of ENDS users were grouped into a class comprising 85% of the sample and characterized by either little/no substance use or moderate alcohol consumption. Conclusions: ENDS use in this sample was not indicative of general exploration with substances, nor was it indicative of isolated tobacco use, but rather more heavy and problematic substance use.