Research examining the demographic and substance use characteristics of illicit drug use in the United States has typically failed to consider differences in routes of administration, or has exclusively focused on a single route of administration--Injection Drug Use (IDU). Therefore, a significant gap exists in our understanding of the degree to which IDUs are different from those who use illicit drugs via other routes, such as oral, inhalation, or smoked (non-IDUs). Data from the 2005–2007 National Survey on Drug Use and Health (NSDUH) were used to compare past-year IDU and non-IDU routes of administration for people who use the three drugs most commonly injected drugs in the US: heroin, methamphetamine, and cocaine. Among past-year users, IDUs were more likely than those using via other routes to be older (aged 35+), unemployed, possess less than a high school education, and reside in rural areas. IDUs also exhibited higher rates of abuse/dependence, perceived need for substance abuse treatment, and co-occurring physical and psychological problems. Fewer differences between IDUs and non-IDUs were observed for heroin users compared to methamphetamine or cocaine users. These results highlight significant differences in demographics, clinical/psychological manifestations, and treatment needs of injection drug users compared to those engaging in other routes of administration.