Objective:Long-term abstinence can be undermined by cessation fatigue—an exhaustion of coping resources attributable to quitting smoking/staying quit. The current study examines the predictive validity of a Cessation Fatigue Scale (CFS; three subscales). Among current smokers, we hypothesized higher fatigue would predict longer latency to both quit initiation and achieving 7-day point prevalence abstinence (7-day PPA). Among recent quitters, we expected higher cessation fatigue would confer greater lapse/relapse risk. Lower rates of abstinence at 2-month follow-up were expected for those with higher fatigue. Method: Current smokers motivated to quit in the next month (n = 301) and recent quitters (n = 242) were assessed biweekly over the course of 2 months. Retention rates were high (>85%). Cox and logistic regression analyses tested hypotheses. Results: Among smokers, greater emotional exhaustion predicted longer delay to achieving 7-day PPA (HR = .53, 95% CI [.40, −.68], p < .001) and lower likelihood of 7-day PPA at 2-month follow-up (OR = .27, 95% CI [.16, −.46], p < .001), even after controlling for nicotine dependence and motivation to quit. Among recent quitters, emotional exhaustion progressively increased over the first 6 weeks since quit initiation. Elevated exhaustion was associated with greater lapse (HR = 1.65, 95% CI [1.06, 2.56], p < .05) and relapse (HR = 2.33, 95% CI [1.37, 3.97], p < .01) risk, and lower likelihood of 7-day PPA at 2-month follow-up (OR = .39, 95% CI [.16, .94], p < .05), even after controlling for nicotine withdrawal and motivation to quit. Conclusions: Cessation fatigue, as measured by the CFS’s emotional exhaustion subscale, prospectively predicted important cessation milestones. Findings suggest that cessation fatigue is a novel process that undermines smoking cessation and a viable target for intervention.