Thymus-derived (T) and bone marrow-derived (B) lymphocytes were isolated from human peripheral blood and cultured with various mitogens and antigens. Purified protein derivative of tuberculin stimulated both purified T and B cells from patients with positive skin reactivity to purified protein derivative but did not stimulate nonimmune lymphocytes. Similarly, both T and B lymphocytes from patients with periodontal disease were stimulated to proliferate when incubated with dental plaque, whereas cells from normal individuals without gingivitis were unresponsive. In contrast, one component of plaque, bacterial endotoxins (lipopolysaccharide), minimally stimulated B lymphocytes from both normal or gingivitis patients. T lymphocytes from patients with periodontal disease were also stimulated by plaque antigen to produce chemotactic lymphokine activity (CTX) for human monocytes. B cells purified by the EAC rosetting method nonspecifically produced CTX without concomitant blastogenesis; however, after dissociation of adherent EAC these immune B cells did not spontaneously produce CTX. Lymphokine synthesis by B cells was not dependent on concomitant blastogenesis. Dissociated B cells from periodontitis patients also produced CTX activity after stimulation with dental plaque antigen. Therefore, both T and B lymphocytes, after stimulation with nonendotoxin antigenic components of plaque, proliferated and produced lymphokines, which are presumed to contribute to the pathogenesis of periodontal disease.