The loss of neuronal immunoreactivity of the cytoskeletal microtubule-associated protein 2 (MAP2) is known to be a marker of - at least - transient functional failure of neurons following ischemia. Because there are no specific neuropathological findings in forensic types of acute hypoxia-ischemia, detection of this relevant cause of death is often complicated and a reliable ischemic biomarker would be of great importance. We therefore investigated the neuronal immunoreactivity of MAP2 in human cases of forensic significance. A control group (n=27) was compared to a group of cases of hypoxia-ischemia (n=45), comprising death due to hanging (n=19), drowning (n=14) and carbon monoxide (CO) poisoning (n=12). Using immunohistochemical staining, the percentage of MAP2-positive neurons in the hippocampus (areas CA1-CA4) and frontal cortex (layers II-VI) was evaluated and compared. The hypoxia-ischemia group showed decreased MAP2 immunostaining in the hippocampal areas CA2-CA4 (P < 0.05) and in cortical layers II-VI (P < 0.001) compared to controls. Most vulnerable regions seem to be the hippocampal CA4 area and cortical layers III-V. Within the hypoxia-ischemia group, death due to CO poisoning was characterized by the lowest MAP2 immunoreactivity. The hypoxic-ischemic groups differ from controls by a distinct decrease of MAP2 immunostaining. Thus, the loss of MAP2 immunoreactivity may support the diagnosis of neuronal injury in forensic types of hypoxia-ischemia, although investigations on postmortem tissue must be interpreted cautiously.