© 2019, Springer Nature Switzerland AG. Background and aim: Providing care to an older adult with a disability has been associated with increased risk to the caregiver’s health, but most previous studies of caregiving and health compare persons who are already caregivers with poorly matched non-caregiving controls and are often based on convenience samples. In this report, we describe the enrollment of persons who transitioned into a family caregiving role while participating in a national epidemiological study. Methods: Participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study were asked on two occasions 9–14 years apart if they were providing care on an ongoing basis to a family member with a chronic illness or disability. Those who answered “no” and “yes”, respectively, to this caregiving question and reported sufficient caregiving responsibilities after their transitions were enrolled in the present study as incident caregivers (N = 251). Participants matched on multiple demographic and health history variables and who reported no history of caregiving were enrolled as non-caregiving controls (N = 251). Results: Among eligible participants, 84% agreed to participate, and 47% of caregivers reported caring for a person with dementia. Descriptive analyses confirmed the success of the matching procedures for balancing the groups on multiple demographic and pre-caregiving health variables. Depressive symptoms and perceived stress increased significantly after the transition to caregiving. Conclusion: Comparable, population-based samples of incident caregivers and matched non-caregivers have been enrolled. Future analyses will examine within-person changes in health and circulating biomarkers as a function of the transition to caregiving.