Abstract Esophageal adenocarcinoma (EAC) is rapidly increasing in incidence in many Western societies, requires demanding treatment, and is associated with a poor prognosis, therefore preventive measures are highly warranted. To assess the opportunities for prevention, we reviewed the available literature and identified seven main potentially preventive targets. Preventive effects were found on the basis of medium-level observational evidence following treatment of gastroesophageal reflux disease (using both medication and surgery) and tobacco smoking cessation, which should be clinically recommended among exposed patients. Nonsteroidal anti-inflammatory drugs appear to prevent EAC, and the limited existing data also indicate a protective effect of medication with statins or hormone replacement therapy in women, but current evidence is insufficient to guide clinical decision-making regarding these drugs. The evidence is presently insufficient to assess the potentially preventive role of weight loss. Whether avoidance of eradication of Helicobacter pylori prevents EAC is not studied, but there is no evidence that such eradication increases symptoms of gastroesophageal reflux or prevalence of erosive esophagitis. The introduction of preventive actions should be tailored toward high-risk individuals, that is, older men with obesity and gastroesophageal reflux disease and individuals with Barrett esophagus rather than the population at large. Cancer Prev Res; 9(11); 828–34. ©2016 AACR.