Lifetime prevalence data show that all three classes of prescription drugs were widely used among the sample. This sample of IDUs reported much higher rates of lifetime nonmedical prescription drug use compared to respondents in the National Survey on Drug Use and Health (NSDUH) conducted in 2004. The prescription drugs involved were OxyContin, Xanax, or Ritalin, as well as the use of atypical drugs such as Quaaludes. The use of these drugs involved such atypical modes of administration as sniffing, smoking, and injection. New polydrug combinations were also found, such as injecting OxyContin and ketamine. These were associated with drug overdoses. Some participants reported transitioning from a prescribed drug to a street drug in the same drug class. Methods of acquiring prescription drugs included peers, illicit "scripts," and street settings. Future research should focus on the extent to which nonmedical prescription drug use occurs in polydrug use and the context of polydrug use. Additional research should also consider the initiation, use, supply, and contexts associated with prescription drug misuse among high-risk youth. The study involved young IDUs recruited in New York City (n=50), New Orleans (n=67), and Los Angeles (n=96) as part of a study examining health risks associated with injecting ketamine. All participants were between the ages of 16 and 29 who had injected ketamine at least once in the past 2 years. Lifetime misuse of prescription drugs was assessed with structured questions that presented participants with a list of 25 prescription drugs and asked whether each drug had ever been used nonmedically. 3 tables and 41 references