A St. Louis encephalitis (SLE) epidemic in Florida during 25 weeks in 1990–1, resulted in 222 laboratory-diagnosed cases, an attack rate in the 28 affected counties of 2·25/100000. Disease risk rose with advanced age, to 17·14/100000 in persons over 80 years, and all 14 fatal cases were in persons over 55 years (median, 70 years). Community serosurveys in Indian River County, the epicenter of the outbreak (attack rate 21/100000), showed acute asymptomatic infections in 3·6% of the persons surveyed, with higher rates in persons with outdoor occupational exposure (7·4%) and in clients of a shelter for the indigent (13·3%). A matched case-control study found that evening outdoor exposure for more than 2 h was associated with an increased risk for acquiring illness (odds ratio [OR] 4·33, 95% CI 1·23–15·21) while a number of recommended personal protective measures were protective. Four SLE patients were dually infected with Highlands J virus, the first reported cases of acute infection with this alphavirus. The case-control study provided the first evidence that a public education campaign to reduce exposure had a protective effect against acquiring the disease.