Background and Purpose: Data on the significance of combined white matter hyperintensities (WMH)/lacunar brain infarcts, and their progression over time for the prediction of stroke are scarce. We studied associations between the progression in combined measures of microvascular brain disease and risk of stroke in the ARIC study (Atherosclerosis Risk in Communities). Methods: Prospective analysis of 907 stroke-free ARIC participants who underwent a brain magnetic resonance imaging (MRI) in 1993 to 1995, a second brain MRI in 2004 to 2006, and were subsequently followed for stroke incidence through December 31, 2017 (median [25%–75%] follow-up 12.6 [8.9–13.4] years). A combined measure of microvascular brain disease was defined at each visit and categorized by progression from first to second brain MRI as no progression; mild progression (increase of ≥1 unit in WMH grade or new lacune), and moderate progression (increase of ≥1 unit in WMH grade and new lacune). All definite/probable ischemic or hemorrhagic incident strokes occurring after this second MRI, and through 2017, were included. Associations between microvascular brain disease, progression in the combined measures, and stroke incidence were studied with Cox proportional hazard models, adjusting for age, sex, race, education level, time from first to second MRI, body mass index, smoking, hypertension, diabetes mellitus, and coronary heart disease. Results: At the second brain MRI (mean age 72), the distribution of the combined measure was 37% WMH grade <2 and no lacune; 57% WMH grade ≥2 or lacune; and 6% WMH grade ≥2 and lacune. No progression in the combined measures was observed in 38% of participants, 57% showed mild progression and 5% showed moderate progression. Sixty-four incident strokes occurred during the follow-up period. Compared with no change in the combined measure, moderate progression of microvascular brain disease was significantly associated with higher risk of stroke (adjusted hazard ratio, 3.00 [95% CI, 1.30–6.94]). Conclusions: Progression of microvascular brain disease, manifesting as both new lacunes and increase in WMHs grade, is related to substantial increase in long-term risk of stroke.