The cause of asthma, which has been linked to a chronic, T-cell-mediated bronchial inflammation, remains unclear. A number of other T-lymphocyte-mediated, chronic inflammatory disorders have been associated with autoimmunity and there are data indicating that autoimmune phenomena might also be present in asthma. Expression of perforin, a cytotoxic molecule produced by lymphocytes, has been implicated in the pathogenesis of autoimmune diseases. We therefore tested the hypothesis that allergic and intrinsic asthma might be associated with an increase in lymphocytes producing perforin by comparing the expression of intracellular perforin in peripheral blood lymphocytes of patients with extrinsic asthma (n = 13), intrinsic asthma (n = 7), and healthy control subjects (n = 18). Lymphocytes were identified using flow cytometry and subdivided into CD3⁺, CD4⁺, CD8⁺, CD16⁺, and CD56⁺ subpopulations after staining with appropriate monoclonal antibodies. The percentage of perforin-positive total lymphocytes was significantly elevated in patients with allergic as well as intrinsic asthma when compared with normal control subjects. Analysis of lymphocyte subpopulations also revealed a significant increase in the percentage of CD3⁺, CD4⁺, CD8⁺, and CD56⁺ cells expressing perforin in allergic asthma and a significant increase in the percentage of CD4⁺ and CD56⁺ cells in intrinsic asthma when compared with healthy control subjects. Perforin expression in CD4⁺ cells in intrinsic asthma was also significantly elevated compared with allergic asthma. We conclude that allergic and intrinsic asthma is associated with increased expression of perforin in T-lymphocyte subsets. Arnold V, Balkow S, Staats R, Matthys H, Luttmann W, Virchow JC, Jr. Increase in perforin-positive peripheral blood lymphocytes in extrinsic and intrinsic asthma.