The opioid epidemic is a significant public health crisis that is often linked to chronic pain management. One ensuing consequence of long-term opioid use for chronic pain is a high potential for opioid misuse and dependence. Although tobacco is commonly used among individuals with chronic pain, it is associated with an increased risk for opioid-related problems. Given the deleterious outcomes of tobacco use in the context of chronic pain, identifying individual difference factors involved in tobacco-opioid relations is of public health importance. Pain-related anxiety, or a tendency to respond to pain sensations with anxiety and fear, maybe an especially important mechanistic factor associated with the relationship between tobacco use severity and opioid misuse. Therefore, the current study examined the moderating role of pain-related anxiety on the relationship between tobacco use severity and opioid misuse and dependence. Participants were 258 tobacco-using adults who endorsed moderate to severe chronic pain and current use of an opioid medication (72.1% female, M = 37.19 years, SD = 10.17). Two hierarchical linear regression analyses were conducted to test main and interactive effects of tobacco use severity and pain-related anxiety for current opioid misuse and severity of opioid dependence. Results indicated a significant moderation effect, such that the relationship between tobacco use severity and opioid misuse and dependence was stronger among individuals with higher (but not lower) pain-related anxiety. These findings build upon the extant literature by demonstrating an interactive effect of tobacco use severity and pain-related anxiety in terms of opioid-related outcomes and suggest that current tobacco users with elevated levels of pain-related anxiety may be at increased risk for opioid misuse and dependence.