Background: Surgical resection is the most effective treatment for patients with isolated esophageal cancer, but the 5-year survival rate is still very poor in spite of recent advances in early diagnosis and extended lymphadenectomy. To identify the high-risk group and the factors affecting postoperative course, we analyzed the prognostic factors including the family history of esophageal cancer in survival after esophagectomy. Methods: A total of 1,553 patients with esophageal squamous cell carcinoma after surgery were the subject of the present study. Thirty-one percent of all these patients have family history of esophageal cancer. The prognostic factors analyzed in this study included age, sex, tumor size, tumor location, lymphadenopathy, histologic type, grade of differentiation, stage of cancer, adjuvant treatments, and family history of esophageal cancer. Results: The overall 3-year and 5-year postoperative survival rates were 43.7% and 26.2%, respectively, for all patients with esophagectomy. The five prognostic factors determined as significant by univariate p value were tumor size, lymphadenopathy, grade of differentiation, stage of cancer, and family history of esophageal cancer. Multivariate analysis showed that the independent prognostic factors were tumor size, grade of differentiation, stage of cancer, and family history of esophageal cancer. Our study also found that patients in groups with mid and upper segment esophageal squamous cell carcinoma, smaller tumor size, earlier stage of cancer, and poor differentiation of tumor cells had a significantly higher rate of positive family history than in the other groups, respectively. Conclusions: Tumor size, grade of differentiation, lymphadenopathy, stage of cancer, and family history of esophageal cancer were identified as prognostic factors after esophagectomy. Family history of esophageal cancer is an important prognostic factor that surgeons should take into consideration when selecting a treatment method. © 2010 The Society of Thoracic Surgeons.