Famotidine is a histamine H2-receptor antagonist. It is widely prescribed in active duodenal ulcers, gastric ulcers, Zollinger-Ellison syndrome, gastroesophageal reflux disease, and erosive esophagitis. The effective treatment of erosive esophagitis requires administration of 20 mg of Famotidine 4 times a day. a conventional dose of 20 mg can inhibit gastric acid secretion up to 5 hours but not up to 10 hours. An alternative dose of 40 mg leads to plasma fluctuations; thus, a sustained release dosage form of famotidine is desirable. The short biological half-life of drug (2.5-4 hours) also favors development of a sustained release formulation. The present study aims to reduce the dosing frequency by using single and combinations of synthetic and natural polymers for preparation of mucoadhesive tablets. Various approaches to combine synthetic (HPMC-K4M, SCMC and sodium alginate) and natural (tragacanth and acacia) hydrophilic polymers have been made to prepare total eight formulations. Further, these formulations were subjected to different evaluation studies like friability, content uniformity, surface pH, wash-off and dissolution tests. All the tests were performed using standard methods. Results for in vitro drug release and wash-off studies suggest that the formulation (FHT) containing HPMC-K4M and tragacanth has shown better mucoadhesive property. Other studies have shown satisfactory results in all eight formulations. Thus, the present investigation suggests the combination of HPMC-K4M and tragacanth, as hydrophilic polymers for preparation of famotidine mucoadhesive tablets.