During iron-limited growth Neisseria meningitidis expresses two transferrin binding proteins, TBP1 and TBP2, with molecular masses of approximately 98 and 65-90 kDa depending on strain. Mixtures of TBP1 and TBP2 (TBP1 + 2) from three meningococcal strains were purified using affinity chromatography and used to determine anti-TBP antibodies in human sera by ELISA. Sera were obtained from healthy individuals, asymptomatic carriers of N. meningitidis and cases of meningococcal disease. Healthy individuals had little detectable antibody to TBPs but sera from carriers and cases exhibited a response demonstrating that TBPs are expressed in vivo during both carriage and disease. The ELISA absorbances produced by each of the individual sera to TBPs from the three meningococcal strains were compared and very high correlation coefficients were obtained, indicating that human anti-TBP antibodies, in contrast to mouse and rabbit antibodies, are cross-reactive between strains. Antibodies to separately purified TBP1 and TBP2 were also detected in both cases and carriers. The IgG and IgM response to TBP1 + 2 was greater in cases than carriers but the mean IgA response was the same. This demonstration of an antibody response that is cross-reactive between TBP types greatly strengthens the case for inclusion of TBPs in a meningococcal vaccine to protect against all serogroups and serotypes.