Interactions of hyaluronic acid (HA) with its binding proteins CD44 and RHAMM (receptor for HA-mediating motility) have been proposed to be important in promoting tumor progression and dissemination. However, a comparative study of their expression patterns in stomach cancer and its associated lesions is not yet available. To address this issue, the combined examinations of pathology, immunocytochemistry and Western blot hybridization were performed on advanced gastric cancer specimens as well as their preneoplastic and non-cancerous counterparts. Alternative CD44 expression was observed in the gastric mucosa with different lesions. CD44 proteins harboring variant exon 6 (CD44 v6) was detected only in cancer tissues with a total positive rate of 14% (10/74). Intracellular RHAMM molecules in Mr 93000 to 95000 were expressed in 3/31 non-cancerous mucosa. RHAMM detection rates increased along with tumor progression. Irrespective of the differences of gross and morphological pattern, majority (54/74) of cancer cases expressed multiple RHAMM isoforms in Mr 40000-45000, 64000, 70000-73000, 85000 and 93000-95000 with the appearance of cell surface immunocytochemical labeling. Among CD44 variant isoforms, v6 is more relevant with malignant transformation of gastric epithelium. Expression of RHAMM, especially the cell surface variants, is closely correlated with tumor progression (P<0.01). Expression of CD44 and RHAMM may benefit the invasion and metastasis of gastric cancer cells presumably in a reciprocal manner.