This adherence study was performed to clarify the trafficking of Hodgkin-Reed-Sternberg (HRS) cells in Hodgkin's disease (HD) and thus try to unravel the peculiar pathways of dissemination in the early stages of this malignant neoplasm. Using non-neoplastic human necropsy or biopsy lymph node as well as tonsillar tissue sections, we have studied the adherence of the KMH-2 and L-428 HD-derived cell lines and have compared it to that of peripheral blood lymphocytes (PBLs). In necropsy lymph nodes, cell lines predominantly adhered to sinuses and paracortex, whilst adhered PBLs were distributed more widely. In biopsy lymph nodes, adhesion to high endothelial venules (HEVs) was rarely observed, whilst cell lines were found to adhere to sinuses. Inhibition by EDTA pretreatment affected adherence to HEVs as well as to sinuses and paracortex to a similar degree. Our findings point to the possible importance of the lymph node sinuses and paracortex in relation to homing of the HRS cells and their dissemination during the early stages of HD. The results suggest a significant primary role of the extracellular matrix of the paracortex and sinuses in the homing of HRS cells, with the HEVs of only secondary importance.