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Opioid misuse constitutes a significant public health problem and is associated with a host of negative outcomes. Despite efforts to curb this increasing epidemic, opioids remain the most widely prescribed class of medications. Prescription opioids are often used to treat chronic pain despite the risks associated with use, and chronic pain remains an important factor in understanding this epidemic. Cannabis is another substance that has recently garnered attention in the chronic pain literature, as increasing numbers of individuals use cannabis to manage chronic pain. Importantly, the co-use of substances generally is associated with poorer outcomes than single substance use, yet little work has examined the impact of opioid-cannabis co-use.The current study examined the use of opioids alone, compared to use of opioid and cannabis co-use, among adults (n = 450) with chronic pain on mental health, pain, and substance use outcomes.Results suggest that, compared to opioid use alone, opioid and cannabis co-use was associated with elevated anxiety and depression symptoms, as well as tobacco, alcohol, cocaine, and sedative use problems, but not pain experience.These findings highlight a vulnerable population of polysubstance users with chronic pain, and indicates the need for more comprehensive assessment and treatment of chronic pain.