: Responses to problem substance use have largely focused on illicit drugs, but reports on rising prescription drug misuse worldwide raise questions about their combined use with alcohol and potential consequences. The current study assessed prevalence of alcohol in conjunction with nonmedical opioid and benzodiazepine use across a nationally representative sample of adults in Brazil. Cross-sectional data on prevalence were estimated from the 2015 Brazilian Household Survey on Substance Use. We estimated past month nonmedical use of benzodiazepines and alcohol and past month nonmedical use of opioids and alcohol among adults who reported any past-year alcohol use. Zero-inflated Poisson models assessed independent correlates of alcohol and nonmedical opioid use, and alcohol and nonmedical benzodiazepine use. Among adults who reported past year alcohol use, 0.4% ( = 257,051) reported past month alcohol and non-medical benzodiazepine use, and 0.5% ( = 337,333) reported past month alcohol and non-medical opioid use. Factors independently associated with co-use of alcohol and benzodiazepines included having depression (adjusted prevalence ratio (aPR):4.61 (95%CI 1.76-12.08)), anxiety (aPR:4.21 (95%CI 1.59-11.16)) and tobacco use (aPR: 5.48 (95%CI 2.26-13.27)). Factors associated with past-month alcohol and opioid use included having experienced physical or a threat of violence (aPR: 4.59 (95%CI 1.89-11.14)), and tobacco use (aPR:2.81(95%CI:1.29-6.12)). Co-use of prescription drugs with alcohol remains relatively rare among Brazilians, but findings point to a unique profile of persons at risk. Results of this study are important in light of changing dynamics and international markets of prescription drugs and the need for more research on use of these substances on a global scale.