Objective: To estimate the burden of encephalitis-associated hospitalizations in the United States for 1998–2010. Methods: Using the Nationwide Inpatient Sample, a nationally representative database of hospitalizations, estimated numbers and rates of encephalitis-associated hospitalizations for 1998–2010 were calculated. Etiology and outcome of encephalitis-associated hospitalizations were examined, as well as accompanying diagnoses listed along with encephalitis on the discharge records. Total hospital charges (in 2010 US dollars) were assessed. Results: An estimated 263,352 (standard error: 3,017) encephalitis-associated hospitalizations occurred in the United States during 1998–2010, which corresponds to an average of 20,258 (standard error: 232) encephalitis-associated hospitalizations per year. A fatal outcome occurred in 5.8% (95% confidence interval [CI]: 5.6%–6.0%) of all encephalitis-associated hospitalizations and in 10.1% (95% CI: 9.2%–11.2%) and 17.1% (95% CI: 14.6%–20.0%) of encephalitis-associated hospitalizations in which a code for HIV or a tissue or organ transplant was listed, respectively. The proportion of encephalitis-associated hospitalizations in which an etiology for encephalitis was specified was 50.3% (95% CI: 49.6%–51.0%) and that for which the etiology was unspecified was 49.7% (95% CI: 49.0%–50.4%). Total charges for encephalitis-associated hospitalizations in 2010 were an estimated $2.0 billion. Conclusions: Encephalitis remains a major public health concern in the United States. Among the large number of encephalitis-associated hospitalizations for which an etiology is not reported may be novel infectious and noninfectious forms of encephalitis. Associated conditions such as HIV or transplantation increase the risk of a fatal outcome from an encephalitis-associated hospitalization and should be monitored. CI= : confidence interval; ICD-9-CM = : International Classification of Diseases , ninth revision, Clinical Modification; IQR= : interquartile range; NIS= : Nationwide Inpatient Sample; RR= : rate ratio; SE= : standard error; WNV= : West Nile virus