We analyzed the prevalence of hemagglutination inhibition (HI) antibodies to St. Louis encephalitis (SLE) virus in wild birds during the 1990 SLE epidemic in Indian River County. The initial presence of SLE HI antibody was associated significantly with modeled drought 15 wk prior, wetting conditions 1 wk prior, and the emergence of the Florida SLE virus vector, Culex nigripalpus, 5 wk prior. Our findings indicated that three factors conspired to create the 1990 epidemic: (1) a large population of susceptible wild birds; (2) severe springtime drought, which facilitated amplification of the SLE virus among the Cx. nigripalpus and a portion of the wild bird population; and (3) continued rainfall and wetting of the land surface in the summer and early fall, which sustained a large, host-seeking Cx. nigripalpus population. The continued biting and reproductive activity of Cx. nigripalpus maintained epizootic transmission throughout the summer and early fall in Indian River County. The high level of SLE virus amplification resulted in spillover transmission to humans. We hypothesize that without the continued reproductive activity of the vector mosquito, brought about by excessive summer and fall wetness, the unprecedented SLE virus amplification and consequent transmission to humans would not have been realized in 1990.