Brief abstinence from smoking impairs cognition, particularly executive function, and this has a role in relapse to smoking. This study examined whether working memory-related brain activity predicts subsequent smoking relapse above and beyond standard clinical and behavioral measures. Eighty treatment-seeking smokers completed two functional magnetic resonance imaging sessions (smoking satiety vs 24 h abstinence challenge) during performance of a visual N-back task. Brief counseling and a short-term quit attempt followed. Relapse during the first 7 days was biochemically confirmed by the presence of the nicotine metabolite cotinine. Mean percent blood oxygen level-dependent (BOLD) signal change was extracted from a priori regions of interest: bilateral dorsolateral prefrontal cortex (DLPFC), medial frontal/cingulate gyrus, posterior cingulate cortex (PCC), and ventromedial prefrontal cortex. Signal from these brain regions and additional clinical measures were used to model outcome status, which was then validated with resampling techniques. Relapse to smoking was predicted by increased withdrawal symptoms, decreased left DLPFC and increased PCC BOLD percent signal change (abstinence vs smoking satiety). Receiver operating characteristic analysis demonstrated 81% area under the curve using these predictors, a significant improvement over the model with clinical variables only. The combination of abstinence-induced decreases in left DLPFC activation and reduced suppression of PCC may be a prognostic marker for poor outcome, specifically early smoking relapse.