White matter microstructural integrity has been related to cognition. Yet, the potential role of specificwhite matter tracts on top of a global white matter effect remains unclear, especially when consideringspecific cognitive domains. Therefore, we determined the tract-specific effect of white matter micro-structure on global cognition and specific cognitive domains. In 4400 nondemented and stroke-freeparticipants (mean age 63.7 years, 55.5% women), we obtained diffusion magnetic resonance imagingparameters (fractional anisotropy and mean diffusivity) in 14 white matter tracts using probabilistictractography and assessed cognitive performance with a cognitive test battery. Tract-specific whitematter microstructure in all supratentorial tracts was associated with poorer global cognition. Lowerfractional anisotropy in association tracts, primarily the inferior fronto-occipital fasciculus, and highermean diffusivity in projection tracts, in particular the posterior thalamic radiation, most strongly relatedto poorer cognition. Altered white matter microstructure related to poorer information processing speed,executive functioning, and motor speed, but not to memory. Tract-specific microstructural changes mayaid in better understanding the mechanism of cognitive impairment and neurodegenerative diseases.