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In 1991, the first epidemic of St. Louis encephalitis (SLE) ever reported in Arkansas resulted in 25 cases in Pine Bluff (attack rate: 44 per 100,000; 95% confidence interval [CI] 28–65). To identify risk factors for SLE viral infection and risk factors for neuroinvasive illness, we conducted a community-based, cross-sectional study of noninfected and asymptomatically infected persons and a case-control study of asymptomatically and symptomatically infected persons. The SLE viral infection rate was similar in all age groups and in all studied census tracts. Risk factors for asymptomatic infection included: living in a low income household (relative risk [RR] = 2.6, 95% CI 1.1–6.0), sitting outside in the evening (RR = 2.1, 95% CI 1.0–4.8), and living in homes with porches (RR = 2.9, 95% CI 0.9–9.3) or near open storm drains (RR = 2.2, 95% CI 1.0–4.9). Compared with asymptomatically infected persons, symptomatic persons were older (odds ratio [OR] for age ≥ 55 years = 13.0, 95% CI 1.2–334) and more likely to have a previous history of hypertension (OR = 8.5, 95% CI 1.1–72). Our results indicate that advanced age is the most important risk factor for developing encephalitis after infection with SLE virus. Hypertension and vascular disease may predispose to neuroinvasive disease, but this epidemiologic study has not ruled out the confounding effects of age.