Objective: To investigate the prognosis of Chinese patients with ESCC after surgery and its correlation with genomic alterations (GAs) to identify potential prognostic markers. Methods: The clinical information, pathological specimens of 50 patients with stage II and III primary ESCC who were surgically resected. Based on overall survival, these patients were divided into the short OS group and the long OS group. Genomic alteration detection in patients with esophageal squamous cell carcinoma using next-generation sequencing. Results: There was no skew in the distribution of gender, smoking, and adjuvant therapy between the long OS group and the short OS group. A total of 372 GAs were detected in the 50 patients with ESCC, with 7 types of GAs, including insertions, deletions, and copy number variations (CNVs), and missense mutations occurred most frequently, with a frequency of >50.0%. Tumor protein 53 was the most commonly mutated gene in the entire cohort followed by cyclin D1, cyclin-dependent kinase inhibitor 2A (CDKN2A), and fibroblast growth factor 19. More CDKN2A loss were detected in the short OS group than in the long OS group. The results of the multivariate analysis after adjustment for clinical factors showed a statistically significant difference in the CDKN2A loss between the two groups. Data obtained from The Cancer Genome Atlas for surgical ESCC for surgical ESCC revealed that the CDKN2A loss may be responsible for the poorer prognosis in postoperative patients with ESCC. Conclusion: In patients with progressive primary ESCC, the poor postoperative prognosis may be epiphenomenally associated with the CDKN2A loss.