This study examined the relationship between sexual orientation and substance use among a nationally representative sample of U.S. college and university students. Data from the 1999 College Alcohol Survey were analyzed to compare marijuana and other illicit drug use among heterosexual, homosexual, and bisexual students. Findings indicate no significant differences in either marijuana or other illicit drug use for homosexual students. However, bisexuals, especially females, were more likely to have used both marijuana and other illicit drugs. These findings underscore the importance of examining bisexuals as a separate group rather than combining them together with homosexuals. The findings also indicate the presence of unique risk and protective factors based on sexual orientation.