Objective: To evaluate the association between brain structural markers and caregiving strain among older informal caregivers.; Design: A secondary data analysis combining data from the Caregiver Health Effects Study (1993-1994) and the Cardiovascular Health Study MRI examination (1992-1994).; Setting: Four United States communities.; Participants: Co-residing spousal caregivers (N = 237; mean age: 76.2 years, SD: 2.2 years).; Measurements: Visually rated ventricular and white matter (WM) grades from magnetic resonance imaging, caregiving strain defined as "emotional or physical strain associated with providing care" for any of 12 activities of daily living (ADLs) and instrumental activities of daily living (IADLs), plus measures of caregiving characteristics and caregiver's health.; Results: Overall, 56% of caregivers reported strain. We detected an interaction where strain was very common (>82%) among caregivers who helped with four or more IADLs, regardless of WM grades, and among caregivers with the worst WM grades (WM grades ≥4), regardless of the number of IADLs they helped with. Among caregivers helping with fewer than four IADLs, having WM grade 4 or greater was associated with a 55% higher prevalence ratio for reporting strain. This association remained statistically significant but was most markedly attenuated by adjustments for: care recipient's memory and behavioral problems, caregiver's depression symptoms, and caregiver's ADL impairment.; Conclusions: Caregiving strain is very common among older informal caregivers who provide help with many IADLs, and among caregivers who help with fewer IADLs, but have manifest signs of white matter pathology. Modern quantitative-neuroimaging studies are needed to evaluate whether more subtle variability in brain structure confers caregiving strain and the related health consequences.