BACKGROUND Esophageal cancer has traditionally been associated with very poor outcomes. A number of therapies are available for the treatment and palliation of esophageal cancer, but little systematic evidence compares the efficacy of different treatment strategies. This meta-analysis aimed to investigate whether treatments in addition to radiotherapy could provide better efficacy and safety. MATERIAL AND METHODS We identified a total of 12 eligible studies with 18 study arms by searching PubMed, the Cochrane Library, EMBASE, and Clinical Trials.gov without time or language restrictions. The final search was conducted on 17 August 2016. We calculated mean differences (MD) and risk ratios (RR) with 95% confidence intervals (CI) for continuous and dichotomous data, respectively. Heterogeneity was calculated and reported using Tau², Chi², and I² analyses. RESULTS Twelve studies with 18 study arms were included in the analysis. Addition of surgery to chemo-radiotherapy resulted in improved median survival time (p=0.009) compared with chemo-radiotherapy alone, but all other outcomes were unaffected. Strikingly, and in contrast with patients with squamous cell carcinomas, the subset of patients with adenocarcinoma who received therapies in addition to radiotherapy showed a significant improvement in median survival time (p<0.0001), disease-free survival (p=0.007), 2-year survival rates (p=0.002), and 3-year survival rates (p=0.01). The incidence of adverse effects increased substantially with additional therapies. CONCLUSIONS This meta-analysis reveals stark differences in outcomes in patients depending on the type of carcinoma. Patients with squamous cell carcinoma should be educated about the risks and benefits of undergoing multiple therapies.