INTRODUCTION Cigarette smoking is the most important risk factor for Crohn's disease (CD). The effectiveness of smoking cessation programs (SCPs) in patients with CD is still poorly understood. METHODS This was a retrospective, observational, single-centre, cohort study of 136 active smokers with mean age 55 years (SD=11), 58% males, including 27 (19.8%) patients with CD who entered the multidisciplinary SCP of the Luigi Sacco University Hospital of Milan from January 2017 through January 2019. A pulmonologist was responsible for the clinical and pharmacological management, while a psychiatrist and a psychologist conducted the counselling and assessed the motivation to quit, anxiety and depression using the Brief Psychiatric Rating Scale (BPRS) and the nicotine dependence with the Fagerström test. Patients were defined as quitters after 12 months. RESULTS Demographic and clinical characteristics, and Fagerström score, did not differ in patients with and without CD. At baseline, patients with CD had a higher BPRS (median: 27, IQR: 22-32; vs 25 and 22-28.5; p=0.03), and a lower motivation to quit score (median: 10, IQR: 9-13; vs 14 and 12-15; p<0.001). After 12 months, the quitting rate of smokers with CD was significantly lower (14.8% vs 36.7%; p<0.022) and the chance of quitting was negatively associated with the baseline BPRS (r=-0.256; p<0.003). Varenicline and nicotine replacement therapy tended to be less effective in patients with CD. CONCLUSIONS The lower efficacy of SCPs in patients with CD might be secondary to a higher prevalence of anxiety and depression. Psychological issue recognition and support should be enhanced to increase SCP effectiveness in CD.