Human sera from healthy volunteers and patients convalescent from meningitis were used to search for widely cross-reactive antigens implicated in vivo protective responses. Using the type strain Neisseria meningitidis B16B6 and a wide variety of both N. meningitidis and N. lactamica strains, several cross-reactive antigens and bactericidal sera were found, although the cross-reactivity patterns did not correlate with bactericidal activity, a total correlation was found between bactericidal activity and reaction with one or two high molecular weight proteins (162 and 138 kDa), and a mouse serum against the purified proteins showed a high bactericidal activity. Our results suggest that the high molecular weight proteins found are immunogenic and cross-reactive, eliciting bactericidal responses during infection and as a result of natural immunity. These proteins should be taken into account in studies for future vaccine formulations.