Cerebral hypoperfusion has previously been associated with mild cognitive impairment and dementia in various cross-sectional studies, but whether hypoperfusion precedes neurodegeneration is unknown. We prospectively determined the association of cerebral perfusion with subsequent cognitive decline and development of dementia. Between 2005 and 2012, we measured cerebral blood flow by 2-dimensional phase-contrast magnetic resonance imaging in participants of the population-based Rotterdam Study without dementia. We determined the association of cerebral perfusion (mL/100mL/min) with risk of dementia (until 2015) using a Cox model, adjusting for age, sex, demographics, cardiovascular risk factors, and apolipoprotein E genotype. We repeated analyses for Alzheimer disease and accounting for stroke. We used linear regression to determine change in cognitive performance during 2 consecutive examination rounds in relation to perfusion. Finally, we investigated whether associations were modified by baseline severity of white matter hyperintensities. Of 4759 participants (median age 61.3 years, 55.2% women) with a median follow-up of 6.9 years, 123 participants developed dementia (97 Alzheimer disease). Lower cerebral perfusion was associated with higher risk of dementia (adjusted hazard ratio, 1.31; 95% confidence interval per standard deviation decrease, 1.07-1.61), similar for Alzheimer disease only, and unaltered by accounting for stroke. Risk of dementia with hypoperfusion was higher with increasing severity of white matter hyperintensities (with severe white matter hyperintensities; hazard ratio, 1.54; 95% confidence interval, 1.11-2.14). At cognitive reexamination after on average 5.7 years, lower baseline perfusion was associated with accelerated decline in cognition (global cognition: β=-0.029, =0.003), which was similar after excluding those with incident dementia, and again most profound in individuals with higher volume of white matter hyperintensities ( value for interaction=0.019). Cerebral hypoperfusion is associated with accelerated cognitive decline and an increased risk of dementia in the general population.