It has been suggested that the steroid receptor coactivatior-3 (SRC-3) gene, also known as AIB1, ACTR, RAC3, p/CIP and TRAM-1, located at 20q12, plays an oncogenic role in several types of human cancers. In this study, we examined the encoded protein expression of SRC-3 and its copy number in 221 human esophageal squamous cell carcinomas (ESCCs). In this ESCC series, the overexpression and increased copy number of SRC-3 gene was detected in 46 and 13% of ESCCs, respectively. In addition, overexpression of SRC-3 was observed more frequently in primary ESCCs in late T stages (T3/T4) than that in earlier T1/T2 stages (P<0.05), but no significant association of expression of SRC-3 and status of lymph node metastases was observed (P>0.05). These results suggest that overexpression of SRC-3, caused by gene amplification/gain or other molecular mechanisms, might provide a selective advantage for the development and local invasion of certain subsets of ESCC. In addition, a significant correlation (P<0.05) of overexpression of SRC-3 with increased cell proliferation (through detection of Ki-67 expression) was observed in these ESCCs. These findings suggest a potential role of SRC-3 in the control of ESCC cell proliferation; such may be responsible, at least in part, for tumorigenesis and/or progression of ESCC.