Resected specimens of 288 primary stomach cancers (175 early cases and 113 advanced cases) and recurrent tumors or biopsy specimens of 21 recurrent or inoperable metastatic stomach cancers were examined immunohistochemically for expression of c-erbB-2 oncogene product. c-erbB-2 protein-positive staining was detected in 6.9, 15.9 and 28.6% of early, advanced and recurrent or inoperable metastatic stomach cancers, respectively, the difference being significant (p < 0.005). Four patients with advanced cancer showed positive staining in metastatic lymph nodes but not in the primary tumors. The results of tissue immunostaining were compared with c-erbB-2 protein levels in sera of the patients measured by an enzyme-linked immunosorbent assay. The levels of this oncogene product were consistently low in the sera of most of the patients with primary stomach cancers, regardless of whether or not c-erbB-2 protein was expressed in the tumor. However, in the recurrent or inoperable metastatic stomach cancers, 5 of 6 patients with c-erbB-2 protein-positive tumors showed elevated levels of c-erbB-2 protein in the serum. After following up c-erbB-2 protein levels in the sera of 3 patients during the period of chemotherapy against recurrent or inoperable metastatic disease, we found that the levels increased only in the late stage. These results suggest that, in stomach cancer, c-erbB-2 protein is likely to be excreted into the serum at a relatively late stage, reflecting systemic spread of the disease.