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ABSTRACT Aims To understand the relations among anxiety disorders and tobacco dependence, withdrawal symptoms, response to smoking cessation pharmacotherapy and ability to quit smoking. Design Randomized placebo-controlled clinical trial. Participants received six 10-minute individual counseling sessions and either: placebo, bupropion SR, nicotine patch, nicotine lozenge, bupropion SR + nicotine lozenge or nicotine patch + nicotine lozenge. Setting Two urban research sites. Participants Data were collected from 1504 daily smokers (>9 cigarettes per day) who were motivated to quit smoking and did not report current diagnoses of schizophrenia or psychosis or bupropion use. Measurements Participants completed baseline assessments, the Composite International Diagnostic Interview and ecological momentary assessments for 2 weeks. Findings A structured clinical interview identified participants who ever met criteria for a panic attack (n = 455), social anxiety (n = 199) or generalized anxiety disorder (n = 99), and those who qualified for no anxiety diagnosis (n = 891). Smokers with anxiety disorders reported higher levels of nicotine dependence and pre-quit withdrawal symptoms. Those ever meeting criteria for panic attacks or social anxiety disorder showed greater quit-day negative affect. Smokers ever meeting criteria for anxiety disorders were less likely to be abstinent at 8 weeks and 6 months post-quit and showed no benefit from single-agent or combination-agent pharmacotherapies. Conclusions Anxiety diagnoses were common among treatment-seeking smokers and were related to increased motivation to smoke, elevated withdrawal, lack of response to pharmacotherapy and impaired ability to quit smoking. These findings could guide treatment assignment algorithms and treatment development for smokers with anxiety diagnoses.