Aggregatibacter actinomycetemcomitans is a non-motile gram-negative facultative anaerobic coccobacillus associated with the etiology of aggressive periodontitis (1). The microorganism can also be detected in the oral cavity of chronic periodontitis patients and periodontally healthy subjects (2). A. actinomycetemcomitans is classified into six serotypes (a–f) based on surface O-polysaccharides, and serotype b is usually correlated with aggressive periodontitis (1), although other serotypes have been associated with diseased patients in certain populations (3,4). Similar to other mucosa-associated gram-negative pathogens, A. actinomycetemcomitans produces a cytolethal distending toxin (CDT; 5,6). Cytolethal distending toxin is a secreted tripartite AB2 toxin [An AB2 toxin is a toxin that has an active toxic subunit (A) represented by CdtB, and a B subunit which binds to the target cell, and is formed in Cdt by the subunits CdtA and CdtC], in which CdtB is the active toxic subunit that exhibits both type I deoxyribonuclease-like and phosphatase activities while subunits CdtA and CdtC seem to bind to target cells and CdtC also aids the delivery of CdtB into cells (6). The CDT triggers a DNA-damage response resulting in cell cycle arrest in G2/M or G0/G1 phase in many epithelial and macrophage cell lines and in T lymphocytes. Interestingly, CDT was not able to affect human periodontal ligament cells, although other fibroblastic cell lines were susceptible (6,7). Although the association of CDT with pathogenesis is not fully understood, this toxin may represent a bacterial adaptation which could affect the interaction between the bacterium and the host immune system in chronic diseases. Mice experimentally challenged with a CDT-deficient Helicobacter hepaticus mutant developed a significantly lower immunoglobulin (Ig)G2c response and failed to mount an IgG1 response (8). Cytolethal distending toxin can partly inhibit the production of proinflammatory cytokines by antigen-presenting cells, although A. actinomycetemcomitans CDT induced the production of interleukin (IL)-1β, IL-6, IL-8 and interferon-γ (IFN-γ) by human monocytes (9,10). In mice model, a Haemophilus ducreyi CDT-deficient mutant induced chancroid lesions similar to the wildtype strain (11). However, a Campylobacter jejuni CdtB-deficient mutant was less invasive in mouse tissues (12), leading to an attenuated inflammatory effect in the animal when compared with the wild-type (13). Furthermore, evidence suggested that the A. actinomycetemcomitans CDT inhibited nitric oxide (NO) production by murine macrophages (7). Very little is known about the humoral immune response to CDT in subjects colonized by producing bacteria. Similar levels of IgG to H. ducreyi CDT complex were observed in the sera of chancroid patients and control subjects, as well as in the sera of periodontitis subjects and control subjects (14). Even though the association between A. actinomycetemcomitans and localized aggressive periodontitis is well established, sera of few localized aggressive periodontitis patients contained antibodies to the A. actinomycetemcomitans CDT (15). We aimed to evaluate the association between the IgG response to A. actinomycetemcomitans serotypes and to CDT subunits in sera of subjects with different periodontal conditions. We also tested whether subgingival colonization by A. actinomycetemcomitans in generalized aggressive periodontitis subjects and induction of an antibody response against the organism would lead to an immune response to CDT subunits and to A. actinomycetemcomitans CDT neutralization by sera. The sera neutralization of localized aggressive periodontitis subjects against CDT activity was also tested.