We conducted a nested case-control study to determine potential risk factors for developing encephalitis from West Nile virus (WNV) infection. Retrospective medical chart reviews were completed for 172 confirmed WNV cases hospitalized in Houston between 2002 and 2004. Of these cases, 113 had encephalitis, including 17 deaths, 47 had meningitis, and 12 were fever cases; 67% were male. Homeless patients were more likely to be hospitalized from WNV compared to the general population. A multiple logistic regression model identified age [odds ratio (OR) 1·1, P<0·001], history of hypertension, including those cases taking hypertension-inducing drugs (OR 2·9, P=0·012), and history of cardiovascular disease (OR 3·5, P=0·061) as independent risk factors for developing encephalitis from WNV infection. After adjusting for age, race/ethnicity (being black) (OR 12·0, P<0·001), chronic renal disease (OR 10·6, P<0·001), hepatitis C virus (OR 23·1, P=0·0013), and immunosuppression (OR 3·9, P=0·033) were identified as risk factors for death from WNV infection.