Our experiments show that (i) EPO-mediated upregulation of AQP4 significantly reduces dilation of the cerebral ventricles in obstructive hydrocephalus pups; (ii) EPO triggers AQP4 expression in ependymal cells and astrocytes; (iii) endothelial angiogenesis induced by EPO is likely the mechanism of enhanced CSF resorption into the blood vessel; and (iv) EPO may represent a feasible approach to potential therapeutic options for hydrocephalus. Here, EPO is linked to obstructive hydrocephalus.