BackgroundPrescription drug misuse (PDM) is highly prevalent among youth in the U.S., and can have serious health consequences. Homeless youth are a particularly vulnerable population with high rates of substance use. However, PDM has not been studied in a sample comprised exclusively of homeless youth. MethodsA sample of 451 homeless youth recruited from drop-in centers in Los Angeles, CA, provided information on substance use, mental health, service utilization, trauma, and sexual risk behavior. Multivariable logistic regression assessed correlates of past month PDM. ResultsNearly 50% reported lifetime PDM and 21.6% reported PDM in the past month. The most frequently used prescriptions in the past month were: opioids only (24.5%), sedatives only (23.4%), and stimulants only (10.6%); 14.9% used some combination of these three types of prescription medications. Homeless youth reported that prescriptions were most commonly obtained for free from friends or relatives (24.5%). Foster care involvement was associated with decreased PDM, while hard drug use, suicidal ideation, and unprotected sex were associated with increased PDM. ConclusionsHomeless youth report high rates of PDM, and access these medications most frequently from friends and family. PDM among homeless youth clusters with other risk factors, including hard drug use, unprotected sex, and suicidal ideation. Surprisingly, foster care history was associated with decreased PDM. Programs aimed at preventing PDM among homeless youth should recognize the clustering of risk behaviors, assess prescription use/access when providing mental health services, and educate the general public about proper disposal of prescriptions.