Spontaneous rosetting of T-lymphocytes to Reed-Sternberg cells has been observed both in vitro and in vivo but its molecular mechanism has not been defined. We have investigated such rosetting using the Hodgkin's cell line L428. L428 expresses high levels of LFA-3 and ICAM-1, both of which are ligands for T-cell adhesion. Monoclonal antibody inhibition of spontaneous rosetting indicated that it is not dependent on the T-cell receptor complex but is largely mediated by interaction of T-cell CD2 (T11/E-rosette receptor) with its ligand LFA-3 on L428 cells. Studies using an alternate assay of adhesion (conjugate formation) confirm the roles of CD2/LFA-3 and also implicate a second mode of binding via LFA-1 on T-cells to ICAM-1 on L428. These data explain the previously reported finding of T-cell rosetting with Reed-Sternberg cells as an exaggeration of normal antigen-independent T-cell adhesion.