Papillon-Lefeèvre Syndrome (PLS) is a rare disease accompanied by palmo-plantar hyper-keratosis and rapidly progressive periodontal breakdown of deciduous and permanent dentition. Two unrelated female PLS patients, four and seven years old, with severe periodontal destruction were examined. Antibody titers against seven strains by the enzyme-linked immunosorbent assay (ELISA), microbial cultures from deep periodontal pockets and mouth rinse samples and immuno-blotting analysis were performed. Titers against Actinobacillus actinomycetemcomitans (A. a.) were found to be high by the ELISA test. Microbial cultures of A. a. were found in high percentage and immunoblotting results against sonicated extracts of an A. a. Y4 strain had similar patterns. All deciduous teeth were extracted from the younger patient, later permanent dentition erupted uneventfully and A. a. colonies could not be detected. However, the older patient did not exhibit improvement with conventional periodontal therapy and antibiotic (minocycline/erythromycin) treatment and A. a. colonies could be consistently cultured. After a subsequent ofloxacin medica-tion, A. a. colony detection was suppressed. Furthermore, a reduction of gingival inflammation and pocket depth were observed. Therefore, A. a. was associated as an important pathogen in the etiology of periodontal disease in these PLS patients.