BACKGROUND AND PURPOSE: White matter hyperintensities (WMHs) found on brain MRI in elderly individuals are largely thought to be due to microvascular disease, and its progression has been associated with cognitive decline. The present study sought to determine patterns of cognitive decline associated with anterior and posterior WMH progression. METHODS: Subjects included 110 normal controls, aged >or=60 years, who were participants in the Duke Neurocognitive Outcomes of Depression in the Elderly study. All subjects had comprehensive cognitive evaluations and MRI scans at baseline and after 2 years. Cognitive composites were created in 5 domains: complex processing speed, working memory, general memory, visual-constructional skills, and language. Change in cognition was calculated using standard regression-based models accounting for variables known to impact serial testing. A semiautomated segmentation method was used to measure WMH extent in anterior and posterior brain regions. Hierarchical multiple linear regression models were used to evaluate which of the 5 measured cognitive domains was most strongly associated with regional (anterior and posterior) and total WMH progression after adjusting for demographics (age, sex, and education). RESULTS: Decline in complex processing speed was independently associated with both anterior (r(2)=0.06, P=0.02) and total WMH progression (r(2)=0.05, P=0.04). In contrast, decline in visual-constructional skills was uniquely associated with posterior progression (r(2)=0.05, P<0.05). CONCLUSIONS: Distinct cognitive profiles are associated with anterior and posterior WMH progression among normal elders. These differing profiles need to be considered when evaluating the cognitive correlates of WMHs.