CD21 (C3dg/EBV receptor) is physically associated on B cells with a complex of proteins that includes CD19 and the widely distributed tetraspan 4 (TM4) family protein CD81 as well as other TM4 proteins (CD53, CD37 and CD82). Monoclonal antibodies (mAb) were generated that blocked homotypic adhesion induced by CD21 ligands in the human B cell line Balm-1. One inhibitory mAb (3A8) was found to recognize the ecto-enzyme gamma-glutamyl transpeptidase (GGT), a membrane protein involved in recycling extracellular glutathione and regulating intracellular redox potential. Molecular associations between GGT and TM4 proteins CD81, CD53 and CD82, in addition to CD21 and CD19, were detected by co-precipitation and co-capping analysis. GGT is expressed on several B and T cell lines independently of CD21 expression. These results demonstrate that GGT is a component of widely distributed TM4 complexes, and that on B cells the GGT-containing TM4 complexes also contain CD19 and CD21.