This study was conducted to determine the clinical significance of neuroendocrine differentiation in cases of T3-T4 node-negative colorectal cancer. Eighty-nine patients diagnosed with T3-T4 node-negative colorectal cancer who underwent curative resection were enrolled. Tumors expressing neuroendocrine markers were classified as either low expression (<or=2% cells staining positive for a neuroendocrine marker) or high expression (>2% cells staining positive for a neuroendocrine marker). Immunohistochemical staining for chromogranin A and synaptophysin revealed high expression in 27 (30.3%) and 69 (77.5%) of the 89 patients, respectively. All tumors that showed high expression of chromogranin A also displayed high expression of synaptophysin. With the exception of preoperative carcinoembryonic antigen, no statistically significant correlation was found between neuroendocrine differentiation and all other clinicopathologic variables. Analysis using the Kaplan-Meier method and multivariate Cox regression model demonstrated that neuroendocrine differentiation for chromogranin A and synaptophysin was not associated with disease-free survival. Therefore, neuroendocrine differentiation markers would not be useful variables for prognostic assessment of patients with T3-T4 node-negative colorectal cancer.