A prospective carriage and serological study was conducted in Burkina Faso during the 2003 meningitis season, which was characterized by hyperendemic Neisseria meningitidis serogroup W135 (NmW135) and serogroup A (NmA) disease. Participants were evaluated five times at monthly intervals. In the presence of moderate NmW135 carriage, we found a low prevalence of putatively protective levels of specific immunoglobulin G (IgG) and serum bactericidal antibody (SBA) against NmW135. Specific IgG concentrations and SBA titers against NmA were relatively high in this recently vaccinated population, while no NmA carriage was detected. NmW135 carriage infrequently induced protective immunity against reference or homologous strains, while natural immunity against NmW135 was frequently lost. A vaccine that is effective against W135 will be beneficial for sub-Saharan Africa.