CD28 is a transmembrane glycoprotein that provides T cells with an essential co-stimulatory signal during antigen presentation. Using flow cytometry, we document here an expansion of CD28- T cells in HIV infection. Whereas the percentage of CD4+CD28+ T cells among total lymphocytes was decreased, a small increase of the percentage of CD4+CD28- T cells was observed. In the CD8+ subset, there was a marked expansion of CD8+CD28- T cells. An increased percentage of CD8+ T cells positive for HLA-DR was found in both CD28+ and CD28- cells. Results were similar for CD38 expression. HIV infection was also distinguished by a shift from LFA-1lowCD28low to LFA-1highCD28high and LFA-1high-CD28neg expression pattern on CD8+ T cells. Negative correlations were found between percentage and absolute number of CD8+CD28+ T cells and several serum parameters usually associated with poor prognosis (IgA, IgE, beta 2-microglobulin and HIV-1 p24 antigen). Thus, HIV infection is characterized by a marked expansion of CD28- T cells with an abnormal expression of activation markers and cell adhesion molecules. In addition, CD8+CD28+, but not CD8+CD28- or total CD8+ T cell numbers, correlated with the levels of established serological markers of disease severity or progression and may, therefore, have predictive value.