Objectives. To evaluate the uptake and effectiveness of tailored smoking cessation support, provided primarily by the practice nurse (PN), and compare this to other forms of cessation support. Methods. Three arm cluster randomized controlled trial conducted in 101 general practices in Sydney and Melbourne involving 2390 smokers. The Quit with PN intervention was compared to Quitline referral and a usual care control group. Smoking cessation pharmacotherapy was recommended to all groups. Outcomes were assessed by self-report at 3- and 12-month follow-up. Uptake of the interventions is also reported. Results. The three groups were similar at baseline. Follow-up at 12 months was 82%. The sustained and point prevalence abstinence rates, respectively, at 3 months by group were: PN intervention 13.1% and 16.3%; Quitline referral 10.8% and 14.2%; Usual GP care 11.4% and 15.0%. At 12 months, the rates were: PN intervention 5.4% and 17.1%; Quitline referral 4.4% and 18.8%; Usual GP care 2.9% and 16.4%. Only 43% of patients in the PN intervention group attended to see the nurse. Multilevel regression analysis showed no effect of the intervention overall, but patients who received partial or complete PN support were more likely to report sustained abstinence [partial support odds ratio (OR) 2.27; complete support OR 5.34]. Conclusion. The results show no difference by group on intention to treat analysis. Those patients who received more intensive PN intervention were more likely to quit. This may have been related to patient motivation or an effect of PN led cessation support.