ABSTRACT. Objective:The purpose of this study was to evaluate associations between prescription drug misuse (PDM) and sexual risk behaviors (SRBs) among adolescents and emerging adults. Method: In a hospital emergency department, 2,127 sexually active 14-to 20-yearolds (61% female) reported on past-year alcohol use severity (using the Alcohol Use Disorders Identifi cation Test-consumption [AUDIT-C]), cannabis use, PDM (n = 422), and SRBs (inconsistent condom use, multiple partners, intercourse following alcohol/other drug use). Results: Bivariately, AUDIT-C score, cannabis use, and PDM of stimulants, opioids, and sedatives were positively associated with each SRB. Because many participants reported PDM for multiple drug classes (i.e., sedatives, stimulants, opioids), participants were categorized as (a) no PDM (n = 1,705), (b) PDM of one class (n = 251), (c) PDM of two classes (n = 90), or (d) PDM of three classes (n = 81). Three hierarchical logistic regression models evaluated the associations of number of classes of PDM with SRBs separately, after accounting for demographics (age, gender, race), AUDIT-C score, and cannabis use. Adding PDM statistically improved each model beyond what was accounted for by demographics, alcohol, and cannabis use. For inconsistent condom use and substance use before sex, PDM of one, two, or three classes was signifi cantly associated with increased odds of these SRBs. PDM of two or three classes was associated with increased odds of reporting multiple partners. Conclusions: Findings suggest that PDM, especially poly-PDM, may be a pertinent risk factor for SRBs among youth. Event-based research could further evaluate how PDM, as well as other substance use, is related to SRBs at the event level in order to inform interventions. (J. Stud. Alcohol Drugs, 75, 259-268, 2014)