OBJECTIVES: Prescription drug abuse has emerged as a major public health threat over the past decade. The role of polydrug use (PDU) of psychotherapeutic drugs is currently not well understood in prescription drug abuse (defined as nonmedical use of prescription drugs-NMUPD). This study aims to characterize NMUPD and examine the role of PDU in contributing to prescription drug abuse. METHODS: The National Survey of Drug Use and Health (NSDUH-2010) was utilized to study a population of noninstitutionalized, civilian Americans, aged 12 years and over for NMUPD. NMUPD was defined as the act of consuming a drug from any of the four drug classes (pain relievers, stimulants, tranquilizers and sedatives) without a valid prescription or with a prescription for the experience or feeling it caused. PDU was defined as the use of two or more prescription psychotherapeutic drugs within the past one year. Associations between PDU and NMUPD were tested with respect to demographic and socio-economic factors. RESULTS: Out of a sample of 5166 individuals who were taking psychotherapeutic drugs, about 29% (n=1493) were engaged in PDU. About 4.47% (n=231) of the sample fit the criteria for NMUPD. About 6.50% (n=97) of the PDU sample (n=1493) were engaged in NMUPD. NMUPD was found to be more common among polydrug-users than monodrug-users (6.5% vs. 3.65%). A Chi-Square test for independence showed a significant association between PDU and NMUPD (χ2=20.167, p<0.0001). Demographically, a majority of the polydrug-users with NMUPD were in the age-group 18-25 years (55%), female (54.64%), single (83.51%), nonhispanic white (77.32%), with high school graduation (60.82%) and income less than $10,000 annually (68.04%).  CONCLUSIONS: PDU is a notable and legitimate risk factor for NMUPD. NMUPD among polydrug-users appears to be more prevalent in a population that is young, mostly female, nonhispanic white, with limited income and education.