Despite the proven association between smoking and high rates of medical morbidity and reduced life expectancy in people with severe mental disorders (SMD), their smoking rates do not decline as they do in the general population. We carried out a non-randomized, open-label, prospective, 9-month follow-up multicentre trial to investigate the clinical efficacy, safety and tolerability of a smoking cessation programme designed for the treatment of patients with SMD in the community under real-world clinical conditions. A total of 82 patients were enrolled. Short-term efficacy: The 12-week 7-day smoking cessation (self-reported cigarettes per day =0 and breath CO levels ≤9 ppm) prevalence was 49.3%, with no statistically significant differences between medications (transdermal nicotine patches 50.0% vs. varenicline 48.6%, chi-square =0.015, P = 1.000). Long-term efficacy: At weeks, 24 and 36, 41.3 and 37.3% of patients were abstinent, with no statistically significant differences between treatments. Safety and tolerability: No patients made suicide attempts or required hospitalization. There was no worsening of the scores on the psychometric scales. In both groups, patients significantly increased weight, without significant changes in vital signs or laboratory results, with the exception of significant decreases in ALP y LDL-cholesterol levels in the varenicline group. Patients under varenicline more frequently presented nausea/vomiting (P < 0.0005), patients under TNP experienced skin reactions more frequently (P = 0.002). Three patients under varenicline had elevated liver enzymes. In conclusion, we have demonstrated that in real-world clinical settings it is feasible and safe to help patients with stabilized severe mental disorders to quit smoking.