Intra-ventricular hemorrhage (IVH) is a critical condition with high rate of morbidity and mortality due to acute hydrocephalus and secondary brain injury. Mechanisms underlying the clinical deterioration are not only related to the appearance of an acute hydrocephalus but also to blood-clot mass effect and the inflammatory effects of blood break-down products which impede local blood flow and exert a direct toxic effect on the peri-ventricular structures leading to chronic hydrocephalus. An effective treatment strategy should aim at IVH fast removal and reduction of blood-clot mass effect. Although external ventricular drainage placement is an intuitive treatment for obstructive hydrocephalus this treatment does not address in total the aforementioned pathophysiological mechanisms underlying secondary brain damage. Intra-ventricular fibrinolysis, with tissue plasminogen activator or urokinase, is a level of evidence B, class IIB treatment which has proved to be beneficial in lowering the mortality rates. Its effectiveness on functional outcome has been assessed on three large meta-analysis and a recent large randomized control trial (CLEAR III). Results from the CLEAR III multicenter trial suggest that a routine extra-ventricular drain, irrigation with alteplase reduced mortality but did not substantially improve functional outcomes compared with irrigation with saline. Protocol-based use of alteplase with extra-ventricular drain seemed safe, therefore such approach may be a potential option in individual cases. Currently no consensus has been reached and extrapolation of data from the literature does not permit to identify a uniform therapeutic approach but merely to outline some rational procedural modalities. Further research and studies are needed to compare the efficacy of the different fibrinolytic agents and protocols on functional outcome.