Twenty dentulous subjects undergoing clinical therapy for severe periodontitis were used to determine the longitudinal effects of bacterial plaque reduction in vitro lymphocyte transformation. The therapy consisted of either complete extractions or partial extractions and periodontal surgery combined with rigorous oral hygiene. Prior to therapy lymphocytes from these subjects responded significantly to Streptolysin O (SLO) but were not transformed significantly by solubilized dental plaque. However, after therapy lymphocytes from these same subjects responded significantly to both solubilized dental plaque and SLO. This indicates that the severe periodontitis patients were specifically unresponsive to solubilized dental plaque prior to therapy. The mechanism of the unresponsiveness is not clear, but probably does not involve serum factors because supplementation of the lymphocyte cultures with pooled homologous plasma from individuals with gingivitis or moderate periodontitis (instead of the patient's autologous plasma) did not significantly change the mean lymphocyte responses to solubilized dental plaque. In addition, lymphocytes from eleven long-term (5--18 yr) edentulous subjects, who were free of oral inflammation, were significantly transformed by solubilized dental plaque. The latter lymphocyte responses and those of the treated periodontitis patients could be due either to the presence of low levels of oral bacteria in the edentulous mouth or to the lymphocyte transformation assay being a measure of previous antigen sensitization rather than current disease status. In either case, lymphocyte transformation to solubilized dental plaque is not a useful diagnostic tool in periodontitis, but should continue to be a valuable research tool for investigating pathological mechanisms in periodontitis.