Introduction: Numerous studies have evaluated the efficacy and safety of varenicline for smoking cessation in smokers in the general population and, to a lesser extent, among the psychiatric population. However, few studies have evaluated varenicline in patients with other addictions. The present study was conducted to assess outcomes of a multimodal treatment for smoking cessation intervention with varenicline in a sample of alcohol and substance use disorders and patients with psychotic disorders. Methods: This was a prospective, multicenter study. The patient sample comprised alcoholics in remission, methadone-maintained patients, and patients with psychotic disorders, all of whom wanted to stop smoking. All participants received multimodal treatment for smoking cessation therapy (psychological therapy plus varenicline). Smoking abstinence and changes in the psychopathological state of patients were assessed at predefined time points during a 12-month follow-up. The probability of tobacco abstinence after one year of treatment was computed using Kaplan-Meier life tables. Results: The probability of abstinence at one year was 0.225 (95% CI: 0.143- 0.319). By group, the probabilities were as follows: patients with psychotic disorders 0.254 (95% CI: 0.118-0.415); alcoholics 0.237 (95% CI: 0.098- 0.409); and methadone-maintained patients 0.177 (95% CI: 0.065-0.335). Patients with previous quit attempts had a higher probability of achieving abstinence at one year (p<0.01). Conclusions: The results of this study support the use of multimodal treatment with varenicline in patients with alcohol addiction in remission, patients on methadone maintenance, and patients with stable psychotic disorders. Previous smoking cessation attempts were predictive of smoking cessation success in these patients.