COS cells transiently transfected with human CD48 were found to bind human PBL, whereas mock or CD7-transfected COS cells failed to bind human lymphocytes. Binding of PBL to CD48 transfectants was almost totally inhibited by either CD48 mAb pretreatment of COS cells or CD2 mAb pretreatment of PBL, implying an interaction between CD2 and CD48. This conclusion was confirmed by the demonstration that a highly fluorescent, multimeric form of rCD2 bound to CD48 transfected COS cells in a CD48-dependent manner. Additional mAb blocking studies revealed that CD48 interacts with the T11(1) region of CD2, the same region of CD2 that binds LFA-3 (CD58). Thus, CD48 and CD58 represent alternative and possibly competing ligands for CD2, although based on blocking studies with soluble CD2, CD48 interacts with CD2 with approximately a 100-fold lower affinity that CD58.