In Houston, we have been monitoring the immune response to West Nile virus (WNV) infection in a large cohort of study participants since 2002. Using enzyme-linked immunosorbent assay techniques, serum from 163 participants was tested for the presence of anti-WNV immunoglobulin M (IgM) and IgG antibodies. We found that 42%, 34%, and 23% of study participants had either positive or equivocal results when tested for anti-WNV IgM antibodies approximately 1, 6, and 8 years post-infection, respectively. Conversely, almost one-half of study participants (46%) had undetectable anti-WNV IgG antibodies by 8 years post-infection. This study is the first study to calculate the slope of the rate of decay of antibodies over time as well as show persistence of detectable anti-WNV IgM antibodies up to 8 years post-infection. These findings warrant additional investigation, particularly the determination of whether persistence of IgM is related to persistent infection with WNV.