The purpose of this prospective study was to evaluate the expression of CD44 splice variant epitopes in human breast cancer and their potential as prognostic indicators. Invasive breast cancer tissues obtained from 91 patients were examined for expression of the standard CD44 antigen and variant CD44 antigens (v5, v6, v7, v7-v8, and v8-v10) by immunohistochemical staining to investigate the relations of these antigens to clinicopathological factors and prognosis. The expression of standard CD44 antigen was detected in 54.9% of 91 patients with primary human breast cancer. The variant epitopes of CD44 examined, i.e., v5, v6, v7, v7-v8, and v8-v10, were expressed in 54.9%, 54.9%, 0%, 34.1%, and 0%, respectively. There was a significant difference in tumor size, lymph nodal status, and degree of lymphatic permeation between patients who were positive for exon v7-v8 and those negative for this variant (p < 0.01). Prognosis was also significantly worse in patients positive for CD44 v7-v8 than in those negative for this variant. However, multivariate analysis with the three prognostic indicators tumor size, lymph nodal status, and the degree of lymphatic invasion, has shown that the expression of CD44 v7-v8 antigen in breast carcinoma was not a significant independent prognostic factor and was closely dependent on lymphatic invasion and nodal status. Fourteen of 31 patients who were positive for CD44 v7-v8 experienced recurrences. The mode of recurrence was lymphatic metastasis in 10 out of these 14 patients. Breast cancer cells expressing v7-v8 CD44 antigen have an extremely high affinity for lymph nodes and lymphatic vessels, and are likely to metastasize to distant lymph nodes even at a very early stage in the progression of this disease. This suggests that not only the anatomical factors but also organ affinity plays an important role in the establishment of lymph nodal metastasis of breast cancer.