We assessed in vitro the lymphocyte blastogenic resp onsess of peripheral blood lymphocytes to antigen extracts of a large battery of oral microorganisms in a population of humans with varying severities of periodontal disease. When the magnitudes and frequencies of statistically positive blastogenic responses to various oral microorganisms were compared, three general patterns emerged. The Actinomyces species proved to be potent stimulators of lymphocyte blastogenesis in most subjects tested, whereas Streptococcus sanguis, Campylobacter, and Eikenella corrodens stimulated few individuals. The response to these organisms correlated poorly with the severity of periodontal disease in the tested patients. However, several gram-negative anaerobic organisms, including Bacteroides asaccharolyticus and Treponema denticola, elicited statistically more frequent positive response in subjects with destructive periodontitis compared with patients with gingivitis. These results, taken together with recent microbiological findings, suggest that the specificity of the lymphocyte blastogenic response to antigens of oral bacteria correlates with the presence of these organisms in the subgingival microflora during various periodontal disease states.