BACKGROUND:Pre-treatment factors that increase smokers' risk of experiencing neuropsychiatric adverse events (NPSAEs) when quitting smoking are unknown. OBJECTIVE:To identify baseline smoker characteristics beyond the history of mental illness that predict which participants were more likely to experience moderate to severe NPSAEs in EAGLES. DESIGN:A prospective correlational cohort study in the context of a multinational, multicenter, double-blind, randomized trial. PARTICIPANTS:Smokers without (N = 3984; NPC)/with (N = 4050; PC) histories of, or current clinically stable, psychiatric disorders including mood (N = 2882; 71%), anxiety (N = 782; 19%), and psychotic (N = 386; 10%) disorders. INTERVENTIONS:Bupropion, 150 mg twice daily, or varenicline, 1 mg twice daily, versus active control (nicotine patch, 21 mg/day with taper) and placebo for 12 weeks with 12-week non-treatment follow-up. MAIN MEASURES:Primary safety outcome was the incidence of a composite measure of moderate/severe NPSAEs. Associations among baseline demographic/clinical characteristics and the primary safety endpoint were analyzed post hoc via generalized linear regression. KEY RESULTS:The incidence of moderate to severe NPSAEs was higher among smokers in the PC (238/4050; 5.9%) than in the NPC (84/3984; 2.1%). Three baseline characteristics predicted increased risk for experiencing clinically significant NPSAEs when quitting regardless of carrying a psychiatric diagnosis: current symptoms of anxiety (for every ~ 4-unit increase in HADS anxiety score, the absolute risk of occurrence of the NPSAE endpoint increased by 1% in both PC and NPC); prior history of suicidal ideation and/or behavior (PC, 4.4% increase; P = 0.001; NPC, 4.1% increase; P = 0.02), and being of White race (versus Black: PC, 2.9% ± 0.9 [SE] increase; P = 0.002; and NPC, 3.4% ± 0.8 [SE] increase; P = 0.001). Among smokers with psychiatric disorders, younger age, female sex, history of substance use disorders, and proxy measures of nicotine dependence or psychiatric illness severity also predicted greater risk. There were no significant interactions between these characteristics and treatment. Smokers with unstable psychiatric disorders or with current, active substance abuse were excluded from the study. CONCLUSIONS:Irrespective of cessation pharmacotherapy use, smokers attempting to quit were more likely to experience moderate to severe NPSAEs if they reported current anxiety or prior suicidal ideation at baseline and were White. In smokers with a psychiatric history, female sex, younger age, and greater severity of nicotine dependence were also predictive. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT01456936.