Objective: Smoking treatment may be improved by clarifying determinants of treatment success. Literature suggests that cognitive measures such as working memory (WM) performance are correlated with success. We hypothesized that WM performance and associated brain activity would predict treatment outcome. Method: Participants included 15 treatment-seeking community-recruited smokers (Mcigs/day = 20.9). Participants enrolled in a smoking-cessation program (nine psychotherapy sessions; 8 weeks of nicotine-replacement patches) and 53% successfully quit smoking. Treatment success was defined as not smoking daily following treatment (confirmed by exhaled CO). Verbal WM was assessed using a 2-back fMRI paradigm. Echoplanar BOLD-FMRI was conducted using a Siemens 3T system. A voxel-wise analysis was used to identify 2-back activation clusters for a functional Region of Interest (ROI) analyses (p20 voxels). Independent-samples t-tests were performed to identify differences between successful/unsuccessful quitters on 2-back performance and brain activity in task-associated regions. Results: Successful quitters exhibited significantly faster mean reaction time (t = −2.56, p = .023; 95% CI [−551.7−48.29]). The functional ROI analysis provided nine significant ROIs (2-back > baseline). Quitters exhibited significantly greater activation in the left precentral gyrus (t = 2.49, p = .027; 95% CI [0.149−2.103]) than unsuccessful quitters. Conclusion(s): Our results are consistent with prior research findings that cognitive persistence is a significant prognostic indicator of smoking cessation outcome. In our study, those who successfully quit smoking exhibited significantly higher scores on an effortful WM challenge, which is often presented to assess cognitive persistence. Further, increased activation in WM-associated brain regions during better performance supports the hypothesis they were exhibiting increased effort.