Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide. It is very urgent to understand the underlying molecular mechanism and develop new therapeutic strategy. Tumor necrosis factor receptor-associated factor (TRAF6), initially identified as a regulator of NF-κB, recently has been found to be involved in cancer by modulating various signaling pathways. However, the function of TRAF6 in ESCC is poorly understood. Here, we found that the expression of TRAF6 was upregulated in ESCC cell lines and clinical samples. Moreover, over-expression of TRAF6 in ESCC cells promoted cell proliferation, while downregulation of TRAF6 impaired the tumorigenicity of ESCC cells in vitro and in vivo. Mechanistically, TRAF6 inhibited cell apoptosis by downregulation of activated caspase 3 and cleaved poly ADP ribose polymerase and upregulation of c-Jun, Bcl2, and c-Myc. Taken together, our study suggested the oncogenic role of TRAF6 in ESCC, and TRAF6 might be an important therapeutic target for ESCC.