BACKGROUND: Chronic pain is a public health problem associated with opioid misuse. Yet, it is important to understand factors underlying opioid misuse in the context of pain. Alcohol use is one factor to consider given past work documenting use of alcohol to manage pain. However, it is unknown whether alcohol use severity exacerbates the relation between pain and opioid misuse. This study sought to examine relations between pain and prescription opioid misuse and the moderating role of alcohol use severity in two online survey studies of individuals with chronic pain. METHOD: Individuals with chronic pain (study 1, n = 364; study 2, n = 437) were administered measures of pain, alcohol use, and opioid misuse. RESULTS: In study 1, there was a significant interaction of pain severity and alcohol use (b = 0.16, p < 0.001). Pain was significantly related to opioid misuse among those with higher (b = 1.50, p < 0.001), but not lower (b=-0.26, p = 0.430) alcohol use. In study 2, there was a significant interaction of pain severity and alcohol use (b = 0.03, p < 0.001). Pain was significantly related to opioid misuse among those with higher (b = 0.74, p < 0.001), but not lower (b = 0.07, p = 0.620) alcohol use. CONCLUSIONS: In two online samples, there was evidence of a novel interaction of pain severity and alcohol use severity in relation to opioid misuse. Although cross-sectional, results replicated in two studies. Pain severity was related to opioid misuse among those with higher but not lower alcohol use. Those who use alcohol, even below suggested cut-offs, may be more likely to misuse opioids when in pain.