Background: La Crosse encephalitis (LAC) is a mosquito-borne illness that primarily affects children. In 1997, an initial cluster of cases was identified by the regional pediatric referral center in East Tennessee. Since that time, public health officials, pediatric infectious disease physicians, infection control nurses, laboratory personnel, entomologists, and Centers for Disease Control and Prevention consultants have collaborated to provide ongoing surveillance activities. Studies comparing LAC cases with non-LAC (no etiologic diagnosis) central nervous system infections have yielded no statistical significance in signs and symptoms or laboratory values. Objective: To determine any differences in signs, symptoms, and/or diagnostic laboratory values between LAC cases and enteroviral central nervous system (EV-CNS) infections. Methods: In 2001, descriptive public health surveillance for LAC was performed concurrent with an outbreak investigation of EV-CNS infections at a pediatric referral center in East Tennessee. All patients being evaluated for suspected meningitis and/or encephalitis were interviewed for signs and symptoms of illness. Patients with positive test results for LAC and negative results for EV or positive results for EV and negative results for LAC were included in the study. Results: Compared with patients with EV-CNS infection, patients with LAC were significantly more likely to have aphasia (P = .001), loss of consciousness (P = .0003), seizure (P = .0003), and admission to the pediatric intensive care unit (P = .02). Presence of fever, headache, vomiting, stiff neck (subjective), photophobia, behavioral changes, confusion, need for mechanical ventilation, age, and sex showed no statistical significance (P > .05). Statistical differences were not demonstrated in cerebrospinal fluid laboratory values (P > .05). Conclusion: Patients with LAC demonstrated more severe symptoms on presentation to the hospital than did patients with EV-CNS infection. A possible advantage of identifying specific viral etiologic factors of pediatric CNS disease by clinical characteristics may be the ability to take advantage of emerging antiviral therapies.