Project Summary The majority of smokers (68%) in the US report a desire to quit 1 and most (55.4%) of the 34 million Americans who smoke make a serious quit attempt each year, primarily on their own (i.e., self-guided quit) and to a lesser extent, with assistance from formal treatment 2. Unfortunately, less than 5% of cessation attempters remain abstinent for 6 or more months 3. Smoking prevalence has stabilized as the remaining population becomes increasingly representative of “at-risk smokers” who are unable to quit 4. Yet, there remains little understanding of the subgroups of "at-risk smokers" and the processes governing relapse among them 5. The experience of prolonged fatigue may be one underrecognized but highly common problem that may help in understanding smoking maintenance and relapse. Prolonged fatigue is defined as self-reported, persistent fatigue lasting 1 month or longer 6, 7. In the US, almost 25% of the general adult population has had fatigue lasting 2 weeks or longer 8; the majority of these persons (59% to 64%) reported that their fatigue has no defined medical cause 8, 9. Emerging work suggests that prolonged fatigue is common among smokers 10 and that nicotine may be used to combat fatigue 11. However, there has been no research directed on prolonged fatigue in relation to actual smoking behavior. Therefore, the present proposal seeks to better understand whether and how individual differences in severity of prolonged fatigue predict smoking behavior during an experimental relapse analogue task. The association between prolonged fatigue severity and smoking behavior during the task, however, may depend on whether individuals are in a period of abstinence as the experience of withdrawal during abstinence may be particularly aversive for those with higher fatigue symptoms, leading to greater urges and lapse behavior for these individuals. That is, even though prolonged fatigue severity has been shown to have trait-like qualities 12, it also has been shown to be sensitive to state effects 13. Consequently, the predictive power of prolonged fatigue severity may be particularly (or perhaps only) evident while the individual is experiencing the stress induced by substance deprivation. Therefore, the current project requires that participants attend two counterbalanced experimental sessions – (1) smoking deprivation (16 hours of smoking abstinence) and (2) smoking as usual – during which fatigue severity during the relapse analogue task will be assessed. The proposed project has a great deal of public health significance because it can help guide the development of novel psychosocial or pharmacologic smoking cessation interventions that target a unique and underrecognized vulnerability process (fatigue) that results in poorer cessation outcomes and ultimately help smokers with prolonged fatigue quit.