The purpose of this study was to discover whether S100A2 expression is associated with late cervical metastasis in patients with stage I and II invasive squamous cell carcinoma of the oral cavity. We retrospectively investigated the clinicopathological parameters and S100A2 expression in surgical specimens taken from 52 patients with T1-2N0M0 invasive squamous cell carcinoma of the oral cavity (OSCC) who had not undergone elective neck dissection or irradiation to the neck. All of the clinicopathological factors and S100A2 expression were compared in terms of late cervical metastasis. In univariate analysis, late cervical metastasis correlated with poor overall survival. A higher rate of late cervical metastasis was observed in patients with S100A2-negative tumors than those with S100A2-positive tumors. Multivariate analysis on late cervical metastasis revealed that S100A2 expression was demonstrated to be the only independent factor for late cervical metastasis. Our results indicate that patients with stage I or II invasive OSCC without S100A2 expression should be considered a high-risk group for late cervical metastasis when a wait-and-see policy for the neck is being considered.