The adapter protein growth factor receptor-bound 2 (GRB2) is essential for various basic cellular functions by mediating the regulation of receptor tyrosine kinase (RTK) signaling, however, little is known about GRB2 expression in esophageal squamous cell carcinoma (ESCC). We sought to characterize GRB2 expression and its relationship with clinicopathological parameters and prognostic significance in ESCC patients. Here, it was presented that GRB2 was overexpressed in cytoplasm in 58.1% (100/172) of ESCC cases by immunohistochemistry. Survival analysis demonstrated overexpression of GRB2 protein was significantly related to poor prognosis of ESCC patients (P = 0.021). Furthermore, overexpression of GRB2 was significantly associated with the lymph node metastases. In addition, subgroup analysis according to lymph node metastasis revealed a shorter disease-free survival (DFS) in the ESCC patients with GRB2 overexpression than the patients with GRB2 low-expression (Means for DFS months: 33.8 versus 52.1). Finally, the significant difference between overexpression of GRB2 and poor survival rates exhibited in univariate analysis (P = 0.022) and multivariate Cox analysis (close to significance, P = 0.065), demonstrated that GRB2 was an independent factor in prognosis of ESCC patients. In conclusion, GRB2 expression status could be as a positive biomarker of ESCC progression and lymph node metastasis.