Introduction: Studies suggest that up to 56% of node-negative patients have tumor deposits in their lymph nodes that are missed by routine pathologic examination. However, few studies differentiate between isolated tumor cells and micrometastases using reproducible criteria, and their prognostic significance has not been established. Methods: We identified 119 patients who had undergone surgical resection for esophageal cancer between 1997 and 2007, and who were classified as node-negative. Relevant paraffin blocks were identified, and 3 additional levels, each 250 μm apart, were cut of all lymph nodes. Isolated tumor cells and micrometastases were defined according to size criteria but additional data and characteristics were recorded. Two slides were made at each level (1 for hematoxylin and eosin, 1 for immunohistochemistry). Results were correlated with survival. Results: One patient was found to have a metastasis (>2 mm), 8 patients (7%) had micrometastases, and 22 patients (18%) had isolated tumor cells. The 5-year survival rates were 60% for patients who remained node-negative, 33% for patients with isolated tumor cells, 40% for patients with micrometastases, and 0 for the patient with a metastasis (P = 0.02). A significant difference was found between node-negative patients versus patients whose lymph nodes contained isolated tumor cells (P = 0.014). Most tumor deposits (71%) were identified on the first additional section. Conclusions: Our results suggest that isolated tumor cells are as important as micrometastases in determining survival in patients with esophageal cancer. This has important implications in the retrieval and pathologic analysis of lymph nodes.