Objective: Interventions are required to redress the disproportionate tobacco-related health burden experienced by persons with a mental illness. This study aimed to assess the efficacy of a universal smoking cessation intervention initiated within an acute psychiatric inpatient setting and continued post-discharge in reducing smoking prevalence and increasing quitting behaviours. Method: A randomised controlled trial was undertaken across four psychiatric inpatient facilities in Australia. Participants (N = 754) were randomised to receive either usual care (n = 375) or an intervention comprising a brief motivational interview and self-help material while in hospital, followed by a 4-month pharmacological and psychosocial intervention (n=379) upon discharge. Primary outcomes assessed at 6 and 12 months post-discharge were 7-day point prevalence and 1-month prolonged smoking abstinence. A number of secondary smoking-related outcomes were also assessed. Subgroup analyses were conducted based on psychiatric diagnosis, baseline readiness to quit and nicotine dependence. Results: Seven-day point prevalence abstinence was higher for intervention participants (15.8%) than controls (9.3%) at 6 months post-discharge (odds ratio= 1.07, p=0.04), but not at 12 months (13.4% and 10.0%, respectively; odds ratio = 1.03, p = 0.25). Significant intervention effects were not found on measures of prolonged abstinence at either 6 or 12 months post-discharge. Differential intervention effects for the primary outcomes were not detected for any subgroups. At both 6 and 12 months post-discharge, intervention group participants were significantly more likely to smoke fewer cigarettes per day, have reduced cigarette consumption by and to have made at least one quit attempt, relative to controls. Conclusions: Universal smoking cessation treatment initiated in inpatient psychiatry and continued post-discharge was efficacious in increasing 7-day point prevalence smoking cessation rates and related quitting behaviours at 6 months post discharge, with sustained effects on quitting behaviour at 12 months. Further research is required to identify strategies for achieving longer term smoking cessation.