Rationale <p>Tobacco dependence is characterized by a high relapse rate. It is thus important to obtain a better understanding of the cognitive precipitants of smoking relapses, and how these are changed under tobacco deprivation. Here, we provide evidence that tobacco deprivation impairs two cognitive processes important for successful smoking cessation: metacognition and cognitive flexibility.</p> Methods <p>In a pre-registered study following a within-subject design, persons who regularly smoke performed behavioral tasks measuring metacognition, motivation for mental effort, cognitive flexibility, and smoking lapses either in saturated or deprived states.</p> Results <p>We found that tobacco deprivation not only increased the preference for immediate rewards but also impaired metacognitive knowledge about these preferences; strikingly, these metacognitive skills were moreover related to individual lapse behavior. While there was no evidence for deprivation effects on mental effort, tobacco deprivation also impaired the ability to overcome dysfunctional cue-reward associations, indicating deficits in cognitive flexibility.</p> Conclusions <p>Taken together, the current findings deepen our understanding of how tobacco deprivation alters cognitive processes contributing to addictive behaviors in tobacco dependence, which may lead to improved interventions for smoking cessation.</p>