Properly conducted, an enrichment step can improve selectivity, sensitivity, yield, and most importantly, significantly reduce the time needed to isolate rare circulating tumor cells (CTCs). The enrichment process can be broadly categorized as positive selection versus negative depletion, or in some cases, a combination of both. We have developed a negative depletion CTC enrichment strategy that relies on the removal of normal cells using immunomagnetic separation in the blood of cancer patients. This method is based on the combination of magnetic and fluid forces in an axial, laminar flow in long cylinders placed in quadrupole magnets. Using this technology, we have successfully isolated CTCs from patients with breast carcinoma and squamous cell carcinoma of the head and neck. In contrast to a positive selection methodology, this approach provides an unbiased characterization of these cells, including markers associated with epithelial mesenchymal transition.