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Human parechovirus (HPeV) infections of the central nervous system (CNS) in children can be associated with severe outcomes such as neonatal sepsis-like illness, meningitis, or paralysis. We sought to determine the prevalence of HPeV CNS infections and clinical presentation in children from the United States.Frozen nucleic acid extracts from enterovirus-negative cerebrospinal fluid (CSF) obtained at the Children's Mercy Hospitals and Clinics, in Kansas City from 2006 (n = 242), 2007 (n = 324), and 2008 (n = 218) were tested by 2-step HPeV real-time reverse transcription polymerase chain reaction. HPeV genotype was determined by sequencing the VP3/VP1 junction. Demographic and clinical data were abstracted from medical records.Overall HPeV was detected in 58/780 (7%) of tested CSF samples; 4/218 (2%) in 2006, 54/320 (17%) in 2007, and 0/242 (0%) in 2008. HPeV (17%) and enterovirus (20%) detection were comparable in 2007. HPeV-3 genotype was detected in 52/53 specimens successfully sequenced. Detection was seasonal (June–October). HPeV-3-CNS-infection occurred at a mean age of 6.6 ± 4.4 weeks and predominantly in males (71%). The most common clinical presentation was sepsis-like syndrome (66%). The most common symptoms were irritability (98%), fever (95%), and nonspecific rash (58.6%), while neurologic manifestations were rare (5%).To our knowledge, this is the first multiyear prevalence report of HPeV CNS infection in the United States. HPeV CNS infection was detected mostly in male infants with sepsis-like illness during the late summer/autumn season. Routine seasonal CSF testing in infants for HPeV plus enterovirus may improve etiologic detection and clinical management of infantile sepsis-like presentations.