All cancer staging systems seek to identify clinical and pathological features that can predict outcome or guide therapy. In particular, a non-invasive method for the early detection of disseminating disease would be of great interest. We investigated the use of cytokeratin genes expression to detect blood metastases from colorectal tumors. Epithelial tumor cells were isolated from whole blood using the monoclonal antibody (MAb) BerEP4 and magnetic beads, and detected by reverse transcription-polymerase chain reaction using oligonucleotides derived from the cDNA sequences of cytokeratins 8, 19 and 20. The sensitivity of this assay was determined by spiking SW620 colon carcinoma cells in normal blood. Using cytokeratin 19 expression we were able to detect 1 epithelial tumor cell in 1 ml of whole blood. The clinical applicability of this technique was explored by evaluating patients with a colorectal carcinoma. Epithelial cells were detected in the blood of 12 out of 23 patients, 2 (20%) of 10 with Astler-Coller stage A or B, and 10 (77%) of 13 with stage C or D cancer. In conclusion, this test is a non-invasive, sensitive, and specific assay for detecting circulating epithelial cells in blood. It may be useful for the early diagnosis of disseminating disease, to determine whether the presence of micrometastatic cells at the time of surgery is correlated with an early relapse and for monitoring adjuvant therapeutic trials.