Non-medical prescription drug use (NMPDU) is common among adolescents and young adults (AYAs) nationwide, with 14.4% reporting misuse in the past year. Little is known about characteristics of college students using NMPDU, including other substance use, such as hookah and tobacco, gender identity, and self-efficacy. The purpose of this study was to understand the relationship between hookah and tobacco use, gender identity, and self-efficacy and NMPDU among college students. College students from two universities completed phone interviews. Of the 275 college students interviewed (response rate 86%), 56% were female, and 75% were Caucasian. Variables included NMPDU, other substance use (hookah, alcohol, marijuana, and tobacco), gender, perceived social norms of NMPDU, and self-efficacy. Logistic regression was performed using a priori dependent variables. Lifetime NMPDU was endorsed by 24% of respondents, and participants most commonly reported misusing prescription stimulants. Lifetime consumption of hookah (p<0.01), recent alcohol use (p<0.05), and lifetime marijuana use (p<0.05) were associated with NMPDU. Tobacco use and self-efficacy were not associated with NMPDU. There was a strong positive relationship between NMDPU and consumption of hookah. These findings may aid in identifying those at risk for NMPDU, an important step for targeting prevention efforts of NMPDU in at-risk populations.