Background: Neuropsychiatric symptoms (NPS) frequently occur in patients with dementia. To date, prospective studies on the course of NPS have been conducted in patients with dementia in clinical centers or psychiatric services. The primary goal of this study is to investigate the course of NPS in patients with dementia and caregiver distress in primary care. We also aim to detect determinants of both the course of NPS in patients with dementia and informal caregiver distress in primary care. Methods/design. This is a prospective observational study on the course of NPS in patients with dementia in primary care. Thirty-seven general practitioners (GPs) in 18 general practices were selected based on their interest in participating in this study. We will retrieve electronic medical files of patients with dementia from these general practices. Patients and caregivers will be followed for 18 months during the period January 2012 to December 2013. Patient characteristics will be collected at baseline. Time to death or institutionalization will be measured. Co-morbidity will be assessed using the Charlson index. Psychotropic drug use and primary and secondary outcome measures will be measured at 3 assessments, baseline, 9 and 18 months. The primary outcome measures are the Neuropsychiatric Inventory score for patients with dementia and the Sense of Competence score for informal caregivers. In addition to descriptive analyses frequency parameters will be computed. Univariate analysis will be performed to identify determinants of the course of NPS and informal caregiver distress. All determinants will then be tested in a multivariate regression analysis to determine their unique contribution to the course of NPS and caregiver distress. Discussion. The results of this study will provide data on the course of NPS, which is clinically important for prognosis. The data will help GPs and other professionals in planning follow-up visits and in the timing for offering psycho-education, psychosocial interventions and the provision of care. In addition, these data will enlarge health professionals' awareness of NPS in their patients with dementia. © 2014 Borsje et al.; licensee BioMed Central Ltd.