The raft marker GM1 is expressed at very low levels at the plasma membrane of resting T cells (GM1dull). In vitro T-cell activation induces synthesis of this lipid, which is then expressed at very high levels (GM1bright) at the membrane of activated/effector cells. By flow cytometry and confocal microscopy, we analyzed the expression and organization of GM1 in a series of 15 patients with CD3+ lymphoproliferative disease of granular lymphocytes (LDGL). We found that GM1bright GL were detectable in fresh blood samples obtained in all LDGL patients, although the range of brightly stained cells was extremely variable. This distinctive in vivo pattern has never been shown in T lymphocytes from healthy individuals or in patients with different chronic T or B lymphoproliferative disorders or active infectious diseases. The low number of cycling cells detected in LDGL patients was always included within the GM1bright GL population. Interestingly, GM1bright GL were demonstrated to contain a higher amount of IFN-gamma as compared to GM1dull GL. These findings allow to distinguish subsets of GL at different levels of activation within the monoclonal CD3+ population. The GM1bright GL subset is likely to be responsible for the renewing of GL and thus for maintaining chronic proliferation.