Background. In the presence of type 2 diabetes (T2DM) or coronary heart disease (CHD), depression is under diagnosed and under treated despite being associated with worse clinical outcomes. Our earlier pilot study demonstrated that it was feasible, acceptable and affordable for practice nurses to extend their role to include screening for and monitoring of depression alongside biological and lifestyle risk factors. The current study will compare the clinical outcomes of our model of practice nurse-led collaborative care with usual care for patients with depression and T2DM or CHD. Methods. This is a cluster-randomised intervention trial. Eighteen general practices from regional and metropolitan areas agreed to join this study, and were allocated randomly to an intervention or control group. We aim to recruit 50 patients with co-morbid depression and diabetes or heart disease from each of these practices. In the intervention group, practice nurses (PNs) will be trained for their enhanced roles in this nurse-led collaborative care study. Patients will be invited to attend a practice nurse consultation every 3 months prior to seeing their usual general practitioner. The PN will assess psychological, physiological and lifestyle parameters then work with the patient to set management goals. The outcome of this assessment will form the basis of a GP Management Plan document. In the control group, the patients will continue to receive their usual care for the first six months of the study before the PNs undergo the training and switch to the intervention protocol. The primary clinical outcome will be a reduction in the depression score. The study will also measure the impact on physiological measures, quality of life and on patient attitude to health care delivered by practice nurses. Conclusion. The strength of this programme is that it provides a sustainable model of chronic disease management with monitoring and self-management assistance for physiological, lifestyle and psychological risk factors for high-risk patients with co-morbid depression, diabetes or heart disease. The study will demonstrate whether nurse-led collaborative care achieves better outcomes than usual care.