To investigate the possible immunomodulatory mechanism of D-penicillamine in Scleroderma (Scl), we analysed the surface phenotype of circulating T lymphocytes in 17 Scl patients, 6 of these studied before and after D-penicillamine treatment, 8 only before and 3 only after treatment. The drug was administered for 6 to 24 consecutive months with a median daily dose of 500 mg. The study of peripheral blood purified T cells was carried out using single-colour immunofluorescence and flow cytometry analysis (Ortho Diagnostic System) with monoclonal antibodies such as OKT4 (CD4, helper/inducer), OKT8 (CD8, cytotoxic/suppressor), OKDR and MLR4 (activated T cells), and Tec-5/9 (CD26, activated T cells with specific helper function for B cell differentiation). All of the patients showed lower CD8+ and higher MLR4+ and DR+ T cells than the controls, while CD26+ and CD4+ circulating T lymphocytes were lower in all of the treated in comparison with all of the untreated patients. A decrease in CD26+, CD4+ and total T cells was also observed after treatment in the 6 patients studied pre- and post-therapy. These results support the hypothesis that D-penicillamine selectively impairs the helper T cell subset in Scl patients.