BACKGROUND: The objective of this study was to determine the past-year prevalence rates and behavioral correlates of co-ingestion of prescription opioids and other drugs among high school seniors in the United States. METHODS: Nationally representative probability samples of high school seniors in the United States were surveyed as a part of the Monitoring the Future (MTF) study. Data were collected in schools via self-administered paper-and-pencil questionnaires during the spring of each cohort's senior year. The sample consisted of five cohorts (senior years of 2002-2006) made up of 12,441 high school seniors (modal age 18), of which 53% were women. RESULTS: The estimated prevalence of any past-year co-ingestion of prescription opioids and other drugs for these cohorts was 4.4%, and 69.8% among nonmedical users of prescription opioids. The substances most commonly co-ingested with prescription opioids included marijuana (58.5%), alcohol (52.1%), cocaine (10.6%), tranquilizers (10.3%), and amphetamines (9.5%). Nonmedical users who co-ingested prescription opioids with other drugs were more likely to report intranasal administration, recreational motives, oxycodone use, and greater subjective high when using prescription opioids than nonmedical users who did not co-ingest prescription opioids and other drugs. CONCLUSIONS: Nearly 7 out of every 10 nonmedical users of prescription opioids reported co-ingestion of prescription opioids and other drugs in the past year. The findings indicate that the co-ingestion of prescription opioids and other drugs by high school seniors in the United States serves as a marker for substance abuse and represents a significant public health concern.