The hypothesis that extranodal malignant lymphomas, such as thyroid, stomach, rectum, ileum and uterus, eventuate from long-standing inflammation is essentialy tested using a monoclonal antibody (HECA-452) to an endothelial-associated antigen selectively expressed by the high endothelim of post-capillary venules (HEVs) normally present in lymph nodes, tonsils and mucosa-associated lymphoid tissues. The presence of HEVs was examined on freshly prepared specimens from 16 cases of extranodal lymphoma of the B-cell type (eight thyroid, three stomach, two rectum, one ileum, one uterus, one tonsil). Control cases included reactive lymph nodes, nodal lymphoma of T-cell type, epithelial neoplasia, bone and soft tissue sarcomas, glioblastoma, thyroid affected by chronic lymphocytic thyroiditis (CLTH), thyrotoxicosis (Grave's disease) or nodular goiter, and salivary gland affected by Sjogren's syndrome (SS). HECA+ HEVs were present in reactive lymph nodes, nodal lymphoma, and all but one case of thyroid, all cases of stomach and all cases of rectal lymphoma, together with all CLTH and SS, both known to be autoimmune diseases. No thyroid, ileal or uterine lymphoma cases had any HECA positive venules. HECA+ venules were present in extranodal lymphomas, either adjoining the lymphoid follicles observed in several cases or in the diffusely proliferating tumor cells. Previous studies have shown that HEVs appeared in association with long-standing inflammation. The present study therefore, suggested that extranodal lymphomas of the thyroid, stomach and rectum evolve in long-standing inflammation, forming HEVs.