We previously reported that T lymphocytes of atopic patients displayed a defect in CD2- and CD3-mediated pathways of cell activation; that defect relied on impairment of interleukin 2 (IL-2) production (Romano, M. F., Valerio, G., Turco, M. C., Spadaro, G., Venuta, S., and Formisono, S., Cell. Immunol. 139, 91, 1992). We have subsequently analyzed T cell response to anti-CD2, -CD3, or -CD28 monoclonal antibodies (mAb) in 40 atopic individuals, including patients subjected to immunotherapy. In the latter group T cell response to anti-CD2 mAbs was normal, while IL-2 production and proliferative response in T lymphocytes stimulated via CD3 was still impaired. Costimulation with anti-CD28 mAb rescued both IL-2 production and proliferative response in all tested patients. Response to CD28-mediated stimulation was more pronounced in atopic than that in normal individuals. Our results indicated that CD28 had a major role in T cell proliferation of atopic patients and provided a model for analyzing CD3/CD28 interactions in regulation of IL-2 gene expression.