Objective: Emerging evidence suggests that adults with chronic pain have poor smoking cessation outcomes, but the exact mechanisms are less understood. This study examined whether depression, anxiety, stress, and then, positive outcome expectancy for smoking mediated the association between pain and smoking relapse during a quit attempt. Methods: This study is a secondary data analysis of a three-armed randomized clinical trial that compared in-person and smartphone-based smoking cessation interventions. Participants (N = 81) self-reported the amount of bodily pain they experienced in the past 4 weeks at baseline. Depression, anxiety, stress, and positive outcome expectancy for smoking were measured daily, via a smartphone app, throughout the first week of the quit attempt, and were aggregated to the week level for analyses. Biochemically verified smoking abstinence was assessed 4 weeks postquit date. Results: Sequential mediation analyses showed that pain was indirectly associated with smoking relapse through greater feelings of stress and then higher expectations that smoking would improve mood (B = 0.22 [95% CI = 0.03, 0.65]). The pathways for depression and anxiety were not significant mediators of pain and smoking relapse. Conclusion: Findings from this study indicate that pain is indirectly associated with smoking relapse through feelings of stress and then positive outcome expectancy for smoking. Smoking cessation treatment for adults who experience high