Statement of the Problem: Insolubility is an important criterion for an ideal root-end filling material to both prevent any microleakage between the root canal and the periradicular space and provide sealing ability.Purpose: Many recent studies have shown that mineral trioxide aggregate (MTA) and calcium-enriched mixture (CEM) have acceptable sealing ability. The purpose of this in vitro study was to evaluate the solubility of these root-end filling materials.Materials and Method: Forty stainless steel ring moulds with an internal diameter of 10±1 mm and a height of 2±0.1 mm were selected. Samples of MTA and CEM were mixed according to the manufacturer’s instructions and inserted into the moulds. The specimens were divided into 4 experimental groups and kept in synthetic tissue fluid (STF) for 2 different time periods (7 and 28 days). The control group contained 8 empty rings. The moulds’ weights were recorded before and after immersion in STF. The changes in the weight of the samples were measured and compared using a two- way ANOVA test at a significance level of 5%. Specimens were evaluated with scanning electron microscopy (SEM) at a magnification of 500×.Results: There was no significant difference in weight changes between MTA and CEM samples (p> 0.05).Conclusion: MTA and CEM have similar solubility in STF in different time periods.