Substance use among individuals receiving prescription opioids for pain may be associated with poorer functioning. The purpose was to examine whether use of substances (i.e., alcohol, marijuana, or tobacco) among individuals prescribed opioids for pain management was associated with pain, psychiatric disorders, and opioid misuse. Patients with non-cancer pain and a new opioid prescription were recruited from two health systems. Participants (N= 827) completed measures regarding pain severity, pain interference, psychiatric symptoms, and substance use. Substance use was common with 58.0%, 26.2%, and 28.9% reporting alcohol, tobacco, and marijuana use, respectively. Use of tobacco or marijuana was associated with poorer functioning. Those with tobacco use had greater pain severity, interference, number of pain sites, and concern for opioid misuse, and were more likely to have probable depression, anxiety, and PTSD. Participants reporting marijuana use were more likely to have higher concern for opioid misuse scores and probable depression, anxiety, and PTSD. Use of alcohol was associated with lower pain severity and interference and fewer number of pain sites. Substance use is common among individuals receiving prescription opioids. Some types of substance use may be related to poorer opioid, pain, and psychiatric functioning. Clinicians prescribing opioids for pain management should assess for substance use, including tobacco, and be aware of the association with poorer functioning. Interventions could target pain, psychiatric symptoms, and substance use simultaneously to optimize outcomes for individuals with pain and substance use.