Lymphangiogenesis-the new growth of lymphatic vessels is an important route for the metastatic spread of human cancer. The receptor tyrosine kinase VEGFR-3 is expressed predominantly on lymphatic endothelium, and activation by its ligands VEGF-C and VEGF-D induces lymhpangiogenesis. VEGF-C, VEGF-D and VEGFR-3 have been found to play an important role in the lymphangiogenesis of several cancers. The present study investigated the expression of these factors by immunohistochemical staining of diagnosis specimens from 38 patients with diffuse large B-cell lymphoma (DLBCL). VEGF-C, VEGF-D and VEGFR-3 were expressed in both lymphoma cells and endothelial cells of blood and lymphatic tissue in all but one patient (who was negative for VEGF-D in lymphoma). There was a significant correlation in the intensity of staining between VEGF-C and -D in lymphoma and blood vessels (P < 0.001), and between the intensity of staining of VEGF-D and the patient International Prognostic Index score (P = 0.049) and borderline significance with overall survival (P = 0.051). Mean microvessel count was 58 (range 23-120), and it increased in association with high-intensity VEGF-C staining in lymphoma cells. Our findings indicate the importance of lymphangiogenic factors in the pathogenesis of DLBCL and suggest a potential therapeutic role for antilymphangiogenesis agents.