Neisserial PilC proteins are key elements in type IV pili biogenesis and adhesion. Two pilC alleles are usually present in Neisseria meningitidis. At least one of the PilC proteins is required for pilus assembly and competence for transformation. In addition, meningococcal PilC1, but not PilC2, modulates adhesiveness, whereas, in N. gonorrhoeae, both alleles are adhesive. The meningococcal pilC genes are differently regulated, and it was shown that the expression of pilC1, but not that of pilC2, is transiently induced by bacteria-cell contact. The aim of this work was to determine whether, besides regulation, PilC1-mediated adhesion was conferred by some specific protein pattern not present in the meningococcal PilC2 protein. We demonstrate first that differences within the primary sequence of the meningococcal PilC1 and PilC2 are responsible for different adhesion phenotypes, thus eliminating the regulation of transcription being solely responsible for the adhesive phenotype of PilC1. To identify the regions of PilC1 responsible for adhesion, we engineered meningococcal strains expressing various PilC1-PilC2 hybrids at the pilC1 locus. Our data demonstrate that the specific PilC1 adhesion-promoting regions are located in the amino-terminal part of the molecule and that several domains within this region probably interact with each other to promote adhesion to human cells.