Between late March and June of 2008, an outbreak of hand, foot, and mouth disease caused by enterovirus 71 occurred in China. In this outbreak, more than 176,000 cases occurred, and at least 40 people died. However, there has been no description of the neuropathologic features of fatal enterovirus 71 infection cases during this outbreak. We report postmortem studies in 2 fatal cases of enterovirus 71 infection with examination of the central nervous system using histopathology, immunohistochemistry, and reverse transcription polymerase chain reaction. Characteristic features of acute encephalitis were found predominantly in the brain stem and spinal cord. Abundant numbers of inflammatory cells with unusual irregularly rod-shaped and lobulated nuclei, which mimicked neutrophil morphology, were found both in abscess-like clusters associated with necrosis, as well as in inflammatory infiltrates. Immunohistochemistry showed that most of these cells were CD68 positive and CD15 negative. Viral antigens were found in the cytoplasm of neurons, neuronal processes, and inflammatory cells, most often associated with glial nodules. The presence of enterovirus 71 was confirmed by reverse transcription polymerase chain reaction and sequencing. Results indicate that immunohistochemistry with CD68 and CD15 may offer some help in the differential diagnosis of brain stem encephalitis caused by enterovirus 71. Postmortem reverse transcription polymerase chain reaction from brain stem tissues, which have already undergone fixation and histologic processing, can be an important diagnostic tool, which may be of particular value in patients who may have been misdiagnosed clinically.