It has been demonstrated that the Porphyromonas gingivalis cysteine proteinases (gingipains) activate and/or degrade a broad range of host proteins. Inactivation of gingipains R prior to infection of mice results in a decrease in the virulence of P. gingivalis. Analysis of mouse, rabbit, and chicken antisera raised to gingipain R1 demonstrated that the hemagglutinin domains of gingipains are very immunogenic; however, immunization of mice with a peptide derived from the hemagglutinin domain did not protect mice from P. gingivalis infection. Our recent studies indicate that immunization of mice with a peptide corresponding to the N-terminus of the catalytic domain of gingipains R results in the generation of an immune response that affords protection of mice from P. gingivalis infection. It is postulated that the protection observed results from the inactivation of the enzymatic activity of gingipains R as a result of antibody recognition of a processing site on the gingipain R precursor.