Objective: To establish the magnitude and time course of the changes in water diffusion coefficient (Dav) following newborn infant brain injury. Methods: Ten newborn infants at high risk for perinatal brain injury were recruited from the neonatal intensive care unit. Conventional and diffusion tensor MRI was performed on three occasions during the first week of life. Regions of injury were determined by evaluating conventional MR images (T1, T2, fluid-attenuated inversion recovery) at 1 week after injury. Dav values were determined for these regions for all three scans. Results: Dav values were decreased in most infants 1 day after injury, but injury was not evident or underestimated in 4 of 10 infants despite the presence of injury on conventional imaging at 1 week. By the third day, Dav values were decreased in injured areas in all infants, reaching a nadir of approximately 35% less than normal values. By the seventh day after injury, Dav values were returning to normal (pseudonormalization). Conclusions: MR diffusion images (for which contrast is determined by changes in Dav) obtained on the first day after injury do not necessarily show the full extent of ultimate injury in newborn infants. Images obtained between the second and fourth days of life reliably indicate the extent of injury. By the seventh day, diffusion MR is less sensitive to perinatal brain injury than conventional MR because of transient pseudonormalization of Dav. Overall, diffusion MR may not be suitable as a gold standard for detection of brain injury during the first day after injury in newborn infants.