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Human metapneumovirus (hMPV) is an established pathogen of the respiratory tract of children and adults. hMPV is related to other paramyxoviruses known to cause encephalitis. Reports suggest that hMPV may cause disease of the central nervous system (CNS).Two groups of patients were studied. The first group consisted of children between birth and 18 years from whom nasal scrapings were obtained between January 2004 and October 2005. hMPV RNA amplification by PCR was done and records were reviewed for clinical and demographic data. The second group consisted of patients with encephalitis referred to the California Encephalitis Project (CEP) for comprehensive diagnostic testing between November 2004 and June 2006.In group 1, 1474 specimens were examined for hMPV RNA. Sixty-three evaluable patients were infected with hMPV of whom 4 (6.3%) had seizures, compared with 145 patients infected with RSV of whom 1 had seizures (0.7%, P = 0.031). Comparing respiratory syncytial virus (RSV) and hMPV infections, there was no significant difference in the occurrence of fever. All children with hMPV infections and seizures were hospitalized and 3 were intubated because of status epilepticus. Group 2 consisted of 205 pediatric cases referred to CEP between November 2004 and June 2006 who had hMPV testing done. hMPV was detected in nasopharyngeal swabs of 5 patients. Neither hMPV RNA nor antihMPV specific IgM were detectable in the CSF from the 5 patients for whom CSF was available.Nine cases of CNS illness temporally associated with the presence of hMPV nucleic acid in the upper airway are described. Compared with children infected with RSV, children with hMPV were significantly more likely to have had a seizure. Our data, in conjunction with previously reported cases suggest that hMPV may be associated with a spectrum of CNS disease ranging from febrile seizures to severe, fatal encephalitis.