Recent studies suggest a neuroprotective function for heme oxygenase 2 (HO2) in acute brain injury and ischemia. HO2, the main enzyme to degrade the pro-oxidant heme, was tested for its neuroprotective ability in postnatal neuronal cell cultures and in a model of collagenase-induced intracerebral hemorrhage. Genetic deletion of HO2 rendered cultured neurons 32% (P < 0.01) more vulnerable to hemin-induced toxicity, increased brain injury volume in mice by 30% (P < 0.05) at day 1 and by 67% (P < 0.05) at day 3, and worsened neurologic functions by 26% (P < 0.05) at day 1 and by 38% (P < 0.05) at day 3 following exposure to free heme liberated from hemorrhage. Together, these findings suggest that HO2 is a crucial neuroprotective enzyme in detoxifying high levels of heme from the brain and that further work is warranted to investigate potential therapeutic strategies that target HO2 in intracerebral hemorrhage.