Background. Enteroviruses are common causes of aseptic meningitis and nonspecific febrile illnesses in young children. During the summer-fall months, enterovirus-infected children are frequently evaluated in emergency room settings to rule out bacterial sepsis and/or meningitis. Objectives. We sought to determine the clinical significance of enterovirus infections in children evaluated for serious febrile illnesses in pediatric emergency rooms during the summer-fall season. Methods. Children admitted to emergency rooms at four university teaching hospitals during a single summer-fall season who required blood culture and/or lumbar puncture to rule out bacterial sepsis/meningitis were prospectively studied. An extensive questionnaire was administered, and specimens of cerebrospinal fluid, serum, urine and throat were tested for enteroviruses by vital culture and PCR. Patients were followed to determine the duration, management and outcome of their illnesses. Results. Of 203 patients studied 173 had no apparent explanation for their illness (e.g. bacterial sepsis, bacterial urinary tract infection, etc.). Of those 173 patients 79 (46%) were infected with enteroviruses, including 33 of 47 (70%) patients with aseptic meningitis, 13 of 25 (52%) patients with nonspecific febrile episodes and 33 of 101 (33%) patients with fever and focal findings (P < 0.0001 for aseptic meningitis vs. fever and focal findings; P 0.0001 for aseptic meningitis vs. combined nonspecific febrile episodes and fever/focal patients). Among 119 hospitalized patients 65 (55%) were enterovirus-infected. Children ≤90 days of age were more likely to be enterovirus-infected (66 of 122; 54%) than children older than 90 days (13 of 51; 25%) (P = 0.0001). Enterovirus-infected children were more likely to be hospitalized as a result of the current emergency room visit (65 of 79 vs. 54 of 94; P = 0.0005) and were more likely to have had an additional hospitalization for the same illness (10 of 79 vs. 1 of 94; P = 0.003). Enterovirus-infected patients also had a shorter period from illness onset to presentation. Enterovirus-infected children were indistinguishable from those without enterovirus infection in their symptoms at onset, signs at presentation and total duration of illness (>7 days in both groups). Enterovirus-infected children were almost all treated with antibiotics (78 of 79; 99%), with 74 of 79 (94%) receiving parenteral antibiotics for a mean of 3.6 days. Conclusions. During the summer-fall months, 39% (79 of 203) of children for whom blood cultures and/or lumbar punctures were performed for suspected bacterial infection had enterovirus infection identified as the only explanation for their illness. Of those patients with no alternative diagnosis, enterovirus infection was confirmed in 46% (79 of 179). The majority of those patients requiring hospitalization were infected with enteroviruses. The use of PCR increases the number of children for whom a specific etiology of illness can be determined and may in the future reduce the hospitalization and use of unnecessary antibiotics in patients with enterovirus infections.