Background: Gastroesophageal reflux disease (GERD) is the most common among gastric disorders and treated by antacids especially proton pump inhibitors (PPIs). Though symptoms are reported to be controlled by PPIs, however the complications like barrettes esophagus, Cancers at GE junction are not studied and reported extensively. In view of symptomatic relief, the long, non-supervised, over the counter medication use has increased. Safety of such long-term has been attempted with the review of available evidence and presentation of a case.Aim: To update available literature on the long-term use of PPIs and possible mechanisms behind adverse events.Materials and Methods: A case of Barrette’s esophagus was presented, with long-term use of PPIs. Detailed history taking of the case was done and another evidence synthesis was done on the effects of the long and short-term use of PPIs. The literature search using Medline, Scopus, Scholar on adverse effects of the use of PPIs was done which were language and date unrestricted.Results: Studies report many adverse effects on short-term (up to 5 years of use, namely: clostridium associated diarrhea, bacterial peritonitis, cholecystitis, pyogenic liver, liver cirrhosis, pneumonia, esophageal inflammations, nocturnal breakthrough acid reflux, interstitial nephritis, drug interaction and nutritional deficiencies mainly of Vitamin B 12 and iron) and long-term use, namely: Concomitant dyspepsia, Barrettes esophagus, osteoporosis, dementia, hypomagnesia, cancers at GE junction.Conclusion: The health care providers and community should be made cautious, larger cohort observational studies are also recommended for more evidence