The present study was undertaken to determine the effect of radiotherapy on subpopulations of peripheral blood T cells from patients with Hodgkin's disease. T cell were purified from each specimen, and proportions and absolute numbers of T lymphocytes bearing receptors for the Fc portion of IgG (TG) and for Fc portion of IgM (TM) were enumerated by rosetting T cells with ox red blood cells (ORBC), which had been coated with anti-ORBC rabbit IgG or IgM, respectively. In untreated patients, the percentage of TG cells was significantly increased, and the percentage of TM cells was significantly decreased when compared with control values. In patients examined after radiotherapy, there was a severe depletion of total T lymphocytes. The percent and absolute values of TM cells were also markedly decreased in comparison with those found in either normal controls or untreated patients. In contrast, relative proportions of TG cells were significantly increased in the same treated patients, but the absolute numbers of these cells were essentially unchanged in comparison with those found before radiation therapy. There was a partial and progressive restoration of the number of TM lymphocytes some years after the treatment, but reduced percentages of TM lymphocytes and increased percentages of TG lymphocytes were still found in patients in continuous complete remission for at least five years or more. Similar alterations of the two T-cell subsets were also found in the peripheral blood of a small group of patients treated with radiation for testicular seminoma. These data clearly demonstrate that radiation therapy has a differential effect on identifiable and distinct subsets of cells in the human T-cell class.