Background: PPIs and H2 Blockers are the most commonly used drugs in clinical practice. Inappropriate prescribing that is, PPIs and H2 Receptor Antagonists that are prescribed without detecting any FDA Approved indications may result in increased therapeutic load and cause pill burden to patients. Hence, a study was conducted to determine the prescribing pattern (rationality and irrationality) of both IV and oral PPIs and H2 Receptor Antagonists in the inpatient department of General Medicine [GM] to create awareness on appropriate prescribing of drugs. Aim and Objective: The primary objective of this study is to assess the rationality of prescribing oral and IV Proton pump inhibitors and H2 Receptor Antagonists. The other objective is to reduce pill burden Methodology: A clinical comparative observational study was carried out in the in-patient department of General Medicine in ESI hospital, Ayanavaram, Chennai for six months of duration. Results: A total of 152 patients who were prescribed with oral and IV PPIs and H2 Receptor Antagonists were gathered during the research period to assess the rationality of drug use and the result constituted that about 94 patients received rational therapy and 58 patients received Irrational therapy based on various aspects such as the duration of drug use and justified indications. Conclusion: Based on the results, a significant irrationality in the use of PPIs and H2 Receptor Antagonists were found. In addition, utmost care should be taken while administering PPIs in patients receiving multiple drugs and other elder patients prone to take combination of drugs to attain a rational therapy. PPIs proven to have lower risks of drug interaction would be the favourable choice in those occasions.