Gastrointestinal cancers have frequently shown neuroendocrine (NE) differentiation, but whether NE differentiation occurs in esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, tissue sections obtained from 43 patients with ESCC from a high-incidence area of Northern China were used for the assessing of NE differentiation by immunohistochemistry using antibody against chromogranin A (CGA). In addition, the malignant characteristics and proliferation capacity of CGA-positive cells were also examined by immunohistochemistry. The clinicopathological significance of these CGA-positive tumor cells in ESCC was assessed. Of 43 ESCC samples, CGAimmunoreactive tumor cells were detected in 10 cases (23.26%). However, the CGA-positive tumor cells were scattered at a very low number among non-immunoreactive tumor cells and were rarely constituted a major part of cancer cell nests. Only 4.65% (2/43) cases showed a high density (>10 cells but <1% of total tumor cell mass) of CGA-positive tumor cells. P53 immunoreactivity was frequently shown, while Ki67 was hard to detect in these CGApositive cells. In addition, no relationship between CGA positivity rate and clinicopathological parameters was found. Thus, we concluded that lowdensity CGA-positive tumor cells can be detected in ESCC, supporting the notion that heterogeneous NE differentiation also exists in tumors that lack neuroendocrine cells in their normal epithelial counterparts.