To study the role of extravascular intracranial pressure (ICP) in the genesis of intracranial hemorrhage in the beagle puppy, we measured ICP in animals on the day of birth, untreated 3-day-old controls, and 3-day-old animals treated from birth with prolactin. Baseline ICP varied substantially in all 3 groups. Only 8% of this variability was attributable to variability in mean arterial pressure and central venous pressure. ICP was lower in the 3-day-old controls, animals at high risk for intracranial hemorrhage after a hypovolemic/hypotensive insult followed by rapid volume expansion, than in the other groups which are at lower risk. Administration of a hyperosmolar insult, intraperitoneal glycerol, to animals whose ICP was relatively high promptly lowered ICP. After this treatment, the risk of intracranial hemorrhage was markedly increased in these previously low-risk groups. We conclude that the normal neonatal decrease in brain water content and the consequent fall in ICP substantially increase the risk of intracranial hemorrhage in the beagle puppy, a model which appears similar in pathophysiology to hemorrhage in the preterm human infant.