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Purpose: We planned this prospective study to detect tumor cells in portal venous blood during a curative operation for colon cancer and to identify its clinical implications. Methods: From August to December 1998, we collected portal venous blood (10 ml) during curative operations on 20 patients with colon cancer. Cytokeratin (CK) 19 and 20 transcripts were amplified using a reverse transcriptase-PCR assay. As a negative control, 10 ml of portal blood from 10 patients who underwent benign surgery were assayed. The HCT-116 colon cancer cell line was used for the positive control. All patients were closely followed until May 2003 (mean follow-up: 55 months). Results: CK 19 was positive in 17 (85.0%) patients, and CK 20 was positive in 6 (30.0%) patients. However, CK 19 was also detected in 8 (66.7%) control patients, whereas CK 20 was negative in all control patients. CK 20 was found to be more relevant to the pathologic stage. During the follow-up period, liver metastases were found in 3 patients (50%) who had shown CK 20 in their portal bloods. Conclusions: CK 20 is found to be more specific than CK 19 in the detection of epithelial cells from portal blood. Moreover, CK 20 is related to the stage and was predictive of hepatic metastases in 50% of the patients with colon cancer. With further accumulation of cases, the prognostic significance of CK 20 for hepatic metastases may be better evaluated.