Background: Support in primary care can assist smokers to quit successfully, but there are barriers to general practitioners (GPs) providing this support routinely. Practice nurses (PNs) may be able to effectively take on this role. Objectives: The aim of this study was to perform a process evaluation of a PN-led smoking cessation intervention being tested in a randomized controlled trial in Australian general practice. Methods: Process evaluation was conducted by means of semi-structured telephone interviews with GPs and PNs allocated in the intervention arm (Quit with PN) of the Quit in General Practice trial. Interviews focussed on nurse training, content and implementation of the intervention. Results: Twenty-two PNs and 15 GPs participated in the interviews. The Quit with PN intervention was viewed positively. Most PNs were satisfied with the training and the materials provided. Some challenges in managing patient data and follow-up were identified. Conclusion: The Quit with PN intervention was acceptable to participating PNs and GPs. Issues to be addressed in the planning and wider implementation of future trials of nurse-led intervention in general practice include providing ongoing mentoring support, integration into practice management systems and strategies to promote greater collaboration in GPs and PN teams in general practice. The ongoing feasibility of the intervention was impacted by the funding model supporting PN employment and the competing demands on the PNs time.