BACKGROUND: Few studies have reported the association between lifestyle factors and prognosis of esophageal squamous cell carcinoma (ESCC) and among these, the effects of habitual areca nut chewing have never been examined. METHODOLOGY/PRINCIPAL FINDINGS: Data from 718 pathology-proven ESCC patients recruited in a multicenter hospital-based case-control study between 2000 and 2008 in Taiwan were analyzed. Clinical and lifestyle information were obtained by chart review and questionnaire survey. Death was confirmed using the National Death Index. The mean age at diagnosis was 59.8 years and 506 (70.5%) patients presented with stage III or IV diseases. The overall 1- and 5-year survival rates were 41.8% and 9.75% respectively. In addition to clinical stage, habitual alcohol drinking was found to be the strongest predictor for ESCC survival, followed by areca chewing and smoking. Compared with non-users, patients who regularly used all three substances (alcohol, areca nut, and cigarette) had 1.52 times the risk of early death (adjusted hazard ratio = 1.52, 95% CI = 1.02-2.27, p = 0.04). In addition, the more the number of substances used, the worse the prognosis of ESCC (adjusted p for trend = 0.01). CONCLUSIONS/SIGNIFICANCE: Our study found that indulgence in more substances is a significant predictor of ESCC survival. Further mechanistic studies are necessary to elucidate how these substances lead to an adverse outcome.