BACKGROUND: Although La Crosse virus (LACV) is one of the most common causes of pediatric arboviral infections in the United States, little has been done to assess its geographic distribution, identify areas of higher risk of disease, and to provide a national picture of its clinical presentation. Therefore, the objective of this study was to investigate the geographic distribution of LACV infections reported in the United States, to identify hot-spots of infection, and to present its clinical picture. METHODS AND FINDINGS: Descriptive and cluster analyses were performed on probable and confirmed cases of LACV infections reported to the Centers for Disease Control and Prevention from 2003-2007. A total of 282 patients had reported confirmed LACV infections during the study period. Of these cases the majority (81 percent) presented during the summer, occurred in children 15 years and younger (83.3 percent), and were found in male children (64.9 percent). Clinically, the infections presented as meningioencephalitis (56.3 percent), encephalitis (20.7 percent), meningitis (17.2 percent), or uncomplicated fever (5 percent). Deaths occurred in 1.9 percent of confirmed cases, and in 8.6 percent of patients suffering from encephalitis. The majority of these deaths were in patients 15 years and younger. The county-level incidence risk among counties (n = 136) reporting both probable and confirmed cases for children 15 years and younger (n = 355) ranged from 0.2 to 228.7 per 100,000 persons. The southern United States experienced a significantly higher (p