Neurodegeneration occurs after intracerebral hemorrhage (ICH) and tissue-type transglutaminase (tTG) has a role in neurodegenerative disorders. The present study investigated tTG expression after ICH and the effects of a tTG inhibitor, cystamine, on ICH-induced brain edema and neurological deficits. This study has two parts. In the first, male Sprague-Dawley rats received an intracaudate injection of 100 microL autologous whole blood or a needle insertion (sham). Rats were killed 3 days later and the brains used for immunohistochemistry, Western blots and real-time quantitative polymerase chain reaction. In the second set, ICH rats were treated intraperitoneally with either a tTG inhibitor, cystamine, or vehicle. Rats underwent behavioral testing and were killed at day-3 for measurement of brain swelling. tTG positive cells were found in the ipsilateral basal ganglia after ICH and most of those cells were neuron-like. Western blot analysis showed a 3-fold increase in tTG in the ipsilateral basal ganglia (p<0.01 vs. sham) after ICH. tTG mRNA levels were also significantly higher (8.5-fold increase vs. sham). Cystamine treatment attenuated ICH-induced brain swelling (day 3: 14.4+/-3.2 vs. 21.4+/-4.0% in vehicle-treated rats, p<0.01), neuronal death and improved functional outcome (forelimb placing score: 47+/-23 vs. 17+/-16% in vehicle-treated rats, p<0.05). ICH induces perihematomal tTG upregulation and cystamine, a tTG inhibitor, reduces ICH-induced brain swelling and neurological deficits.