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Background: 5A's counselling is recommended for screening and treating patients with smoking addiction. The emergency department (ED) setting might be a suitable environment for conducting interventions for smoking cessation. The present study aims to determine the feasibility and effectiveness on smoking cessation of 5A's counselling administered to ED patients by nurses., Methods: Parallel group randomized trial assessing 5A's counselling for smoking cessation vs. usual care at a University Hospital in the North of Italy. The primary end-point was prevalence of tobacco-free patients. The secondary outcomes at 6- and 12-month follow-up were (i) consecutive past 30-day smoking abstinence; (ii) past 7-day 50%, or more, decrease in daily tobacco consumption over baseline; and (iii) number of attempts to quit smoking., Results: A total of 480 patients were randomized to intervention (n = 262) or usual care (n = 218). Intention to treat analysis displayed no differences in primary and secondary outcomes between groups. A slight but not statistically significant enhancement in cessation was recorded in the intervention group [relative risk (RR) = 1.04, 95% confidence interval (CI) = 0.58-1.87] at 6 months, whereas a reversed observation at 12 months (RR = 0.86, 95% CI = 0.50-1.47). Similar results were obtained for the secondary outcomes. Per protocol analysis increased the size of the results. Of the 126 smokers receiving counselling, 18 were visited and treated at the local smoking cessation centre, with 12 of them successfully completing the treatment., Conclusion: The results of this study indicate that the ED is not a suited environment for 5A's counselling., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Public Health Association.)