Caffeine is frequently administered to human pre-term newborns although its neurological impact has not been fully evaluated. In the present study performed in mice, we examined the effects of caffeine administration on neonatal excitotoxic lesions of the periventricular white matter, which mimics several aspects of human periventricular leukomalacia. In this model, caffeine exposure did not worsen white matter lesions. These data suggest that neonatal caffeine administration might not affect clastic lesions in pre-term infants.