We conducted a case-control study to determine risk factors for developing encephalitis among West Nile virus cases when compared with age-, gender and race/ethnicity-matched hospitalized controls. In the multivariable conditional logistic regression analysis, we identified the following independent risk factors associated with being an encephalitis case: hypertension (OR 4.0; P = 0.005), immunosuppressing conditions (OR 5.6; P = 0.001) and cardiovascular disease (OR = 28.3; P < 0.001). Individuals with these comorbidities should be targeted for education on protecting themselves from mosquito exposures.