West Nile virus (WNV) infection may be associated with fever, neurologic disorders, and acute flaccid paralysis as a final clinical outcome. In spite of the numerous WNV infection outbreaks in Africa, Eurasia, Australia, and North America and notwithstanding an intense research effort for developing effective anti-WNV vaccines, currently no immunopreventive or therapeutic approaches are available. Moreover, antigenic cross-reactivity among flaviviruses can make difficult WNV serodiagnosis. Here we analyze the primary sequence of WNV polyprotein searching for peptide modules that might be utilized to design targeted diagnostic tools and anti-WNV vaccines for use in humans. To this aim, we applied the low-similarity hypothesis, according to which rare peptide sequences are more likely immunogenic than frequent peptide sequences. We report on a set of peptide sequences unique to the WNV, the immunogenic potential of which appears to be confirmed by immunological data cataloged at the Immune Epitope Data Base resource.