BACKGROUND: Accumulating evidence links blood pressure variability (BPV) with white matter hyperintensities (WMH) and stroke. The longitudinal association between BPV with late onset depression (LOD) and cognitive decline remains unexplored. METHODS: Prospective cohort study of 2812 participant's age 65 years (median age 72 years, 63.6% female) without dementia or stroke. Serial clinic visits assessed blood pressure, cognitive function, depression disorder, and depressive symptoms. A brain magnetic resonance imaging (MRI) substudy was performed in 1275 persons to examine possible associations with WMH. RESULTS: The interaction between symptomatic LOD and systolic BPV was associated with cognitive decline on the Isaac Set Test [slope -4.45; 95% confidence interval (CI) -8.92 to -0.16, p = 0.04], Benton Visual Retention Test (slope -0.89; 95% CI -1.77 to -0.01, p = 0.049), Mini Mental State Examination (slope -1.08; 95% CI -1.86 to -0.30, p = 0.007) and Finger Tapping Test (slope -7.53; 95% CI -13.71 to -1.34, p = 0.017) but not Trail Making Test-A or -B/A. The MRI substudy demonstrated that systolic BPV was associated with cognitive decline via interactions with depression and total WMH volume, but this was not dependent on either deep or periventricular WMH volumes. CONCLUSIONS: The findings show that the interaction between systolic BPV with symptomatic depression and WMH increases cognitive decline in persons 65 years of age. Future work could extend these findings by examining systolic BPV in relation to cognitive decline and WMH in older populations with depression.Read less <