A progressive significant decrease of CD28 surface antigen expression on CD4+ (mean, 90, 86, 79, 68% in stages I, II, III, and IV, respectively, versus 96% in normals), as well as on CD8+ T lymphocytes (mean, 38, 32, 31, and 29% in stages I, II, III, and IV, respectively, versus 47% in normals) was observed during HIV-1 infection. The increase of cytotoxic/suppressor T cells, in both percentage and absolute numbers, that was observed in almost all HIV-1 patients, was associated with an increase of the CD8+ cells lacking the CD28 surface antigen. The loss of CD28 antigen expression was parallel to the increase of CD38, human leukocyte antigen (HLA)-DR, and CD45RO antigen expression on T lymphocytes throughout the disease. Furthermore, a positive significant correlation within the CD4+ but not the CD8+ subset was observed between the percentage of cells lacking the CD28 antigen and the percentage of cells expressing the HLA-DR and CD38 antigens, a finding suggesting that the loss of CD28 antigen expression on CD4+ lymphocytes may be associated with T-lymphocyte activation. Patients treated with zidovudine showed no significant differences in the percentages of either CD4+CD28+ or CD8+CD28+ T-cell subsets when compared to untreated patients. These phenotypic changes may be associated with the functional defects of T lymphocytes in HIV-1 infected individuals.