AbstractBackground Nearly 10% of U.S. 12th graders report high-intensity drinking (10+ or 15+ drinks in a row), but the extent to which these drinkers also engage in nonmedical use of prescription drugs (NMUPD) is largely unknown. This study examined the associations between different thresholds of past two-week high-intensity drinking and past-month NMUPD among U.S. 12th graders. Methods The sample consisted of eleven nationally representative cross-sections of 12th graders in the Monitoring the Future study (2005-2015) who answered questions on past two-week drinking behaviors and past-month nonmedical use of prescription opioids, sedative, stimulants, and tranquilizers (N = 26,502 respondents). Results High-intensity drinking during the past two-weeks was associated with an increased risk of past-month NMUPD. The odds of NMUPD were four times larger among 12th graders who indicated drinking 15 or more drinks on at least one occasion (AOR = 4.43, 95% CI = 3.18, 5.01) relative to those who had 0 to 4 drinks during the past two-weeks, after adjusting for relevant covariates. These associations were similar across different classes of prescription drugs and tended to be stronger among non-white respondents. A sub-analysis revealed simultaneous co-ingestion of alcohol and NMUPD was more prevalent among high-intensity drinkers. Conclusions More than 1 in every 4 U.S 12th graders who engage in high-intensity drinking (15+ drinks in a row) also report NMUPD. Given the greater likelihood of simultaneous co-ingestion of alcohol and prescription drugs among high-intensity drinkers, adolescent substance use interventions need to address the risks associated with mixing alcohol and prescription drugs.