The present study was conducted in mice to validate a double blood infusion model of intracerebral hemorrhage (ICH) that does not use anticoagulant. We investigated the effect of intrastriatal infusion of blood on hematoma volume, neurologic function, brain edema and swelling, and markers of neuroinflammation and oxidative DNA damage. Anesthetized C57BL/6 adult male mice were infused in the left striatum with 4 μl of blood over 20 min at 0.2 μl/min; the needle was left in place for 7 min, and the remaining 6 μl of blood was then infused over 30 min. The injection needle was slowly withdrawn 20 min after the second injection. Sham-operated control mice received only needle insertion. The hematoma produced in this model was primarily restricted to the striatum, and the mice demonstrated severe neurologic deficits that appeared within 60 min and remained evident at 72 h. Brain water content and swelling were significantly increased and were associated with a marked increase in ICH-induced neutrophil infiltration, microglial/macrophage and astrocyte activation, cytochrome c release, and oxidative DNA damage. Other groups have mixed the anticoagulant heparin with the infused blood, an agent that could affect in vivo clot formation. We believe that this double blood infusion model that does not use anticoagulant improves upon the procedure and provides an easy and reproducible alternative for inducing ICH in mice; it should be useful for studying the pathophysiology of ICH and for testing potential pharmaceutical and surgical interventions.