Objective Caregivers of persons with dementia play an important and economically valuable role within society, but many may do so at a considerable cost to themselves. Knowing which caregivers have the highest risk of developing a mental disorder may contribute to better support of ultra-high-risk groups with preventive interventions. This study aims to describe the incidence of depression and anxiety disorders in caregivers and to identify its significant predictors. Design Prospective cohort study with a follow-up of 24 months. Participants 181 spousal caregivers of persons with dementia without a clinical depression or anxiety disorder at baseline. Setting Memory clinics, case management services, and primary care settings in the Netherlands. Measurements The onset of depression and anxiety was measured every 3 months with the MINI International Neuropsychiatric Interview, a structured diagnostic instrument for DSM-IV mental disorders. Potential predictors were assessed at baseline. Results 60% of the caregivers developed a depressive and/or anxiety disorder within 24 months: 37% a depression, 55% an anxiety disorder, and 32% both disorders. Sub-threshold depressive symptoms (Wald χ2 = 6.20, df = 1, OR: 3.2, 95% CI: 1.28-8.03, p = 0.013) and poor self-reported health of the caregiver (Wald χ2 = 5.56, df = 1, OR: 1.17, 95% CI: 1.03-1.34, p = 0.018) at baseline were significant predictors of disorder onset. Conclusion Spousal caregivers of persons with dementia have a high risk to develop a mental disorder. Indicators related to the caregiver's (mental) health rather than environmental stressors such as patient characteristics or interruption of caregivers' daily activities predict disorder onset and can be used to identify caregivers for whom supporting preventive interventions are indicated.