Esophageal adenocarcinoma (EAC) is etiologically associated with gastroesophageal reflux disease (GERD). There is evidence to support the sequence GERD, Barrett's esophagus (BE), dysplasia, and finally EAC, with being implicated in each step to EAC. On the other side of this relation stands the hypothesis of the protective role of against EAC. Based on this controversy, our aim was to review the literature, specifically original clinical studies and meta-analyses linking infection with EAC, but also to provide our personal and others' relative views on this topic. From a total of 827 articles retrieved, 10 original clinical studies and 6 meta-analyses met the inclusion criteria. Original studies provided inconclusive data on an inverse or a neutral association between infection and EAC, whereas meta-analyses of observational studies favor an inverse association. Despite these data, we consider that the positive association between infection and GERD or BE, but not EAC, is seemingly a paradox. Likewise, the oncogenic effect of infection on gastric and colon cancer, but not on EAC, also seems to be a paradox. In this regard, well-designed prospective cohort studies with a powered sample size are required, in which potential confounders should be taken into consideration since their design.