Harris County, Texas, is an endemic area of St. Louis encephalitis (SLE); and an active surveillance program that monitors SLE virus activity in mosquitoes, birds, and humans has been in place there for the past 28 years. In June of 2002, West Nile (WN) virus appeared in Houston and quickly spread throughout the region. This report describes the results of 12 years of SLE surveillance in Harris County and the contrasting pattern of WN virus activity, when it arrived in 2002. Our data indicate that both SLE and WN viruses can coexist, despite their ecologic, antigenic, and genetic similarities, and that both viruses will probably persist in this geographic region.