Objective The 5-year survival rate of patients with esophageal squamous cell cancer (ESCC) is very low. However, long-term aspirin use has been suggested to have an adjuvant therapeutic effect. We therefore investigated the effect of long-term aspirin use before ESCC diagnosis on postoperative patient survival. Methods We carried out a retrospective cohort study of patients who underwent esophageal cancer resection in our hospital from 2008 to 2018. Patients were divided into an aspirin group (n = 79) and control group (n = 79), and were followed up until December 2019. We analyzed the clinicopathological and follow-up data of the patients during hospitalization, and the cyclooxygenase-2 (COX-2) protein expression levels by immunohistochemistry, and related these to postoperative survival. Results Patients who took aspirin had significantly lower survival rates than those who did not. COX-2-negative patients had better survival than patients with either low or high COX-2 expression levels. T stage was the only independent predictor of survival in patients who took aspirin. Conclusions Long-term regular use of aspirin before diagnosis had an adverse effect on postoperative survival in patients with ESCC. Different COX-2 protein expression levels were associated with significantly different postoperative survival rates, with COX-2-positive patients having the poorest survival.