Objective To determine the past-year prevalence rates and correlates of simultaneous co-ingestion of prescription stimulants and other substances among US high school seniors. Methods Nationally representative probability samples of US high school seniors were surveyed as a part of the Monitoring the Future study. The sample consisted of five cohorts including a total of 12?431 high school seniors (modal age: 18?years) and represented a population that was 53% female. Results Among past-year nonmedical users of prescription stimulants (n?=?835), the estimated prevalence of any past-year simultaneous co-ingestion of prescription stimulants and other substances was 64.4%. The substances most commonly co-ingested with prescription stimulants included marijuana (51.1%) and alcohol (48.4%). Nonmedical users who co-ingested prescription stimulants with other substances were more likely to report non-oral routes of administration, recreational motives and greater subjective high when using prescription stimulants than nonmedical users who did not co-ingest prescription stimulants with other substances. Conclusions The majority of past-year nonmedical users of prescription stimulants reported simultaneous co-ingestion of prescription stimulants and other substances. The findings indicate that co-ingestion of prescription stimulants and other substances is a pervasive behavior among US adolescents who engage in nonmedical use of prescription stimulants and should be carefully considered in future clinical practice and research. Copyright © 2014 John Wiley & Sons, Ltd.