The complement cascade is activated and contributes to brain damage after intracerebral hemorrhage (ICH). The present study investigated ICH-induced brain damage in complement C3-deficient mice. This study was divided into 2 parts. Male C3-deficient and C3-sufficient mice received an infusion of 30-microl autologous whole blood into the right basal ganglia. In the first part of our study, mice were killed 3 days later for brain water content measurement. Behavioral assessments including forelimb use asymmetry and corner turn tests were also preformed before and after ICH. In the second part of the study, brain heme oxygenase-1 (HO-1) was measured by Western blot analysis and immunohistochemistry 3 days after the infusion. We found that brain water content in the ipsilateral basal ganglia 3 days after ICH was less in C3-deficient mice compared to C3-sufficient mice (p < 0.05). The C3-deficient mice had reduced ICH-induced forelimb use asymmetry deficits compared with C3-sufficient mice (p < 0.05), although there was no significant difference in the corner turn test score. Western blot analysis showed that HO-1 contents were significantly lower in C3-deficient mice (day 3: 2024 +/- 560 vs. 5140 +/- 1151 pixels in the C3-sufficient mice, p < 0.05). We conclude that ICH causes less brain edema and behavioral deficits in complement C3-deficient mice. These results suggest that complement C3 is a key factor contributing to brain injury following ICH.