Widespread use of meningococcal AC polysaccharide (MACP) vaccines has raised concerns about induction of hyporesponsiveness to C polysaccharide. Whether meningococcal C conjugate (MCC) vaccine overcomes any immunologic refractoriness following MACP vaccination in adults was investigated. University students vaccinated 6 months previously with MACP vaccine were randomized to receive MACP or MCC vaccine, and antibody responses were compared with those of previously unvaccinated students receiving MACP or MCC vaccine. In students primed with MACP vaccine, MCC vaccine induced significantly higher IgG and serum bactericidal antibody levels than did a second dose of MACP vaccine. Responses to a second dose of MACP vaccine were significantly lower than to the first dose. Previous receipt of MACP vaccine reduced serum bactericidal antibody but not IgG responses to MCC vaccine compared with those in previously unvaccinated students. This confirms that MACP vaccine induces immunologic hyporesponsiveness to C polysaccharide in adults, but this can be overcome with MCC vaccine. Repeated vaccination with MACP vaccine may be ineffective, and MCC vaccines should provide better long-term protection.