Aim: To compare the solubility of 5 different root canal sealers in water and in artificial saliva in 24, 48 and 72 hours. Methodology: For standardized rings were filled with epoxy resin (AH-Plus), Silicon based (Roekoseal), Calcium hydroxide based (Apexit plus), MTA based (MTA Fillapex), Zinc oxide eugenol (Prime Dental). These samples were then immersed in distilled water and artificial saliva for 24 hrs, 42 hrs and 72 hrs. The weight loss of the sample was determined by comparing the weight pre test and post test. The data was calculated and analysed using one way ANOVA test. Result:Among all resin based root canal sealer (AH-Plus) has showed less solubility in water and artificial saliva after 24hr, 48hrs and 72 hrs followed by Silicon based sealer- Roekoseal, Calcium hydroxide based – Apexit Plus, MTA based – MTA Fillapex, Zinc oxide eugenol sealer – prime dental. Zinc oxide eugenol based sealer has shown more solubility in saliva than in water. MTA Fillapex has shown more solubility in water than all other sealers. Conclusion: AH-Plus has shown less solubility than all other sealers independent of any medium used, MTA Fillapex has shown more solubility in water. Zinc oxide eugenol has shown more solubility in saliva.