Survivors of acute lymphoblastic leukemia (ALL) can develop neurocognitive deficits and leukoencephalopathy. On-therapy and follow-up MRI examinations of the brain for 173 ALL survivors were reviewed for leukoencephalopathy. At follow-up, the survivors also underwent neurocognitive testing and brain diffusion tensor imaging (DTI). DTI parameters were associated with leukoencephalopathy in multiple regions of the brain. Although there were no associations between neurocognitive performance and leukoencephalopathy, increased mean diffusivity (MD) in certain fiber tracts was associated with neurocognitive impairment. DTI, in particular MD, may better detect loss of white matter integrity associated with neurocognitive deficits in ALL survivors than leukoencephalopathy.