This study is designed to observe the immune reaction in rats after acute carbon monoxide (CO) poisoning. We observed brain injury, cognitive impairment, a variety of microglias and expression of immune factors, including major histocompatibility complex II (MHCII), CD4, vascular cell adhesion molecule-1 (VCAM-1) and interferon-gamma (IFN-gamma) in the brain tissues of CO-poisoned rats. Then relationships between cognitive impairment and immune factors were explored. We found that there were extensive neuronal degeneration and necrosis in the brains of CO-poisoned rats, and the escape latency of the CO Group in a Morris water maze became significantly longer than that of the Control Group (11.63 +/- 3.54s vs. 7.06 +/- 3.13s, p < 0.05) after six days of CO poisoning. Microglias, as immune effector cells, underwent activation and proliferation which reached 35.0 +/- 5.7 cells per five high-power fields (HPF) in the seventh day after CO poisoning, but 20.3 +/- 2.9 cells/5HPF in the Control Group (p < 0.05). Expression levels of immune factors increased in the brains of CO-poisoned rats. VCAM-1-positive cells peaked in quantity the first day, IFN-gamma-positive cells and MHCII-positive cells the third day and CD4-positive cells the seventh day. The results indicate that immune reaction plays an important role on CO-mediated neuropathology.