Statement of the Problem: Alkaline pH can affect the physical and chemical properties and sealing ability of apical plug material. Calcium hydroxide is used in non-vital teeth as an intracanal medication to complete disinfection of root canals. It raises the pH of environment to alkaline value.Purpose: The aim of this in vitro study was to evaluate and compare the effect of alkaline pH on the sealing ability of calcium-enriched mixture (CEM) cement and mineral trioxide aggregate (MTA) apical plugs.Materials and Method: Seventy single-rooted human maxillary anterior teeth were randomly divided to two experimental groups for Angelus MTA and CEM cement (n=30) and two control groups (n=5). Each group was divided into two subgroups of 15 for neutral and alkaline pH, and 1 negative and 1 positive control groups of 5. The root canals were cleaned and shaped by using ProTaper rotary system (Dentsply Maillefer; Ballaigues, Switzerland) and the terminal 3mm of the roots were resected. Then, MTA and CEM cement were condensed in apical region with 3mm thickness. The samples were exposed to two environments with different pH values of 13 and 7.4. The leakage was assessed by using the fluid filtration technique at 1, 7, 14, 30 days intervals. Data were analyzed by the repeated measures MANOVA.Results: There was no statistically significant difference in the rate of microleakage between neutral and alkaline pH of CEM cement and MTA (p> 0.05). The sealing ability of MTA in an alkaline pH of 13 was significantly less than CEM cement in this pH (p< 0.05).Conclusion: An environment with alkaline pH had no adverse effect on the sealing ability of MTA and CEM cement used as apical plugs. CEM cement had better sealing ability in alkaline pH.Key Words: Alkaline pH; Apical Plug; Calcium Enriched Mixture Cement; Fluid Filtration; Mineral Trioxide Aggregate; Microleakage; Sealing Ability