Endoscopic resection is a less invasive treatment than esophagectomy for superficial esophageal squamous cell carcinoma, but patients with lymph node metastasis need additional treatment after endoscopic resection. The purpose of this study was to establish a set of indicators to identify superficial esophageal squamous cell carcinoma patients at a high risk of metastasis. In all, 271 superficial esophageal squamous cell carcinoma esophagectomy cases were reviewed retrospectively. The relationships between clinicopathological parameters and immunohistochemical findings (p53, cyclin D1, EGFR and VEGF) on tissue microarrays, on the one hand, and lymph node metastasis were assessed by univariate and multivariate logistic regression analyses. Patients with intraluminal masses and ulcerated masses had a high risk of lymph node metastasis. Patients with superficial esophageal squamous cell carcinoma (1) thinner than 1200 μm; (2) confined to the mucosa; (3) with submucosal invasion <250 μm; (4) with submucosal invasion ≥250 μm but with negative VEGF expression and well/moderately differentiated or basaloid histology; or (5) with submucosal invasion ≥250 μm but with weak VEGF expression and well-differentiated histology had almost no risk of lymph node metastasis. We recommend endoscopic resection for all erosive, papillary and plaque-like superficial esophageal squamous cell carcinomas where endoscopic resection is clinically feasible, and esophagectomy for all other erosive, papillary and plaque-like cases and all intraluminal masses and ulcerated tumors. No additional treatment is needed for endoscopic resection cases with superficial esophageal squamous cell carcinoma (1) thinner than 1200 μm; (2) confined to the mucosa; (3) with submucosal invasion <250 μm; (4) with submucosal invasion ≥250 μm but with negative VEGF expression and well/moderately differentiated or basaloid histology; or (5) with submucosal invasion ≥250 μm but with weak VEGF expression and well-differentiated histology. These clinical and pathological criteria should enable more accurate selection of patients for these procedures.