Tailored health interventions can be more effective in eliciting positive behavior change than generic interventions, but the underlying neural mechanisms are not yet understood. Here, 91 smokers participated in a functional magnetic resonance imaging session and a tailored smoking-cessation program. We found that increases in activation in self-related processing regions, particularly dorsomedial prefrontal cortex, to tailored messages predicted quitting during a 4-month follow-up.