Objective: To determine the extent of pre- and intraoperative hematogenic tumor cell dissemination in patients undergoing liver resection for metastatic colorectal cancer. Summary Background Data: For patients with hepatic metastases of colorectal cancer, liver resection is the only potentially curative therapy. However, 38% to 53% of patients develop extrahepatic tumor recurrence, probably caused by tumor cells disseminated before or during surgery not detected by current staging systems. Methods: Blood samples harvested before, during, and after surgery from 41 patients and bone marrow samples from 30 patients undergoing resection liver metastases of colorectal cancer were analyzed for disseminated tumor cells using cytokeratin 20 reverse transcriptase-polymerase chain reaction. Results: Tumor cells were detected in the blood samples of 26 of the 41 patients (63.4%). Tumor cells were detected significantly more often during surgery than before or after surgery. Intraoperative tumor cell dissemination was detected in 41.7% of patients undergoing resection two or more liver segments but on 14.3% of patients undergoing resection of one liver segment. Compared with resection of primary colorectal cancer, major liver resection carries an increased risk for intraoperative tumor cell dissemination. Conclusions: Detection of disseminated tumor cells in patients undergoing liver resection for metastases of colorectal cancer using cytokeratin 20 reverse transcriptase- polymerase chain reaction might help to identify patients at high risk for tumor recurrence who may benefit from adjuvant therapy. Major liver resection of metastases leads to frequent intraoperative tumor cell shedding, possibly preventable by alternative surgical strategies.