A significant fraction of human glycosyl-phosphatidylinositol-anchored Ag CD59, CD55, CD48, and CDw52 is present in several cell lines tested (HPB-ALL, Jurkat, HL-60, Raji) in very large noncovalent complexes relatively resistant to dissociation by detergents. These complexes also contain some (glyco)lipids, such as these bearing the CD15, CDw17, and CDw65 determinants, and several intracellular components including protein tyrosine kinases and probably several of their potential substrates. Preclearing of the detergent lysates with different antibodies indicated that all these components are present jointly in a common single type of complexes the size of which is around 100 nm (molecular mass in the range of at least tens of thousands kilodaltons) as determined by ultrafiltration and gel chromatography. These results indicate the existence of cell-surface domains, specifically enriched in the above listed components, that may play a critical role in the so far poorly understood phenomenon of cell activation mediated through many different glycosyl-phosphatidylinositol-anchored (glyco)proteins and glycolipids.