Tumor progression after curative resection of colorectal cancer is caused by tumor cell dissemination, currently undetected by standard clinical staging techniques. The detection of disseminated tumor cells could help to identify a patient subgroup at risk for disease relapse who could benefit from adjuvant therapy. In addition, the significance of lymphogenic compared with hematogenic colorectal cancer cell dissemination is unknown. However, this knowledge would strongly influence the development of future therapeutic regimes. The purpose of this study was to determine the extent of colorectal cancer cell dissemination in lymph nodes compared with blood and bone marrow. Using a CK 20-reverse transcription (RT)-PCR assay, we examined 279 lymph nodes, blood, and bone marrow samples from 20 patients with colorectal cancer. Of 16 patients (11 patients stage I, 5 patients stage II) with histopathologically tumor-free lymph nodes: 14 patients (10 patients stage I, 4 patients stage II) were found to have tumor cells in paracolonic lymph nodes; 12 patients (8 patients stage I, 4 patients stage II) were found to have tumor cells in the lymph nodes along the mesentery vessels; and, remarkably, 6 patients (4 patients stage I, 2 patients stage II) were found to have tumor cells in the apical lymph nodes. In contrast, tumor cells were detected in only two blood and three bone marrow samples of these patients. Thus, lymphogenic tumor cell dissemination is a very common and early event in colorectal cancer, preceding hematogenic tumor cell dissemination. In addition, our data strongly suggest that the detection of tumor cells in the apical lymph node by CK 20-RT-PCR has prognostic relevance. Our results underline the therapeutic importance of meticulous lymph node dissection and demonstrate that the detection of lymphogenic or hematogenic tumor cell dissemination by CK 20-RT-PCR will significantly improve current tumor staging protocols.