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Hand, foot and mouth disease (HFMD) is caused by enterovirus. The virus may exist in secretions.Five neonates had symptoms of fever and maculopapular rashes involving face, trunk, breech, arms, and legs, especially scattering on palms and feet. Blood, oropharyngeal fluid, urine, and cerebrospinal fluid (CSF) samples were collected and detected for further diagnoses with the consent of the infants’ parents. Some of them suffered aseptic meningitis.They were diagnosed as HFMD with CSF enterovirus positive.All of them continued breastfeed. Water bag was used during the pyrogenic stage. Antibiotics were administrated at first and withdrawn as soon as possible.None of them developed into brainstem encephalitis or pulmonary edema and they all recovered well.HFMD is more common in neonates than it has been thought. Enterovirus may exist in neonatal CSF and cause CSF cell to increase similar to purulent meningitis. Medical history, physical examination, and CSF enterovirus detection are important in making correct diagnosis. Unlike bacterial infection, HFMD is a self-limited disease. Once HFMD is determined and bacterial infection is ruled out, antibiotics should be avoided.