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Aims and objectives:The aim of the present study was to determine the effect of different intracanal medicaments on the apical seal of BioRoot root canal sealer (RCS). Materials and methods: One hundred permanent single-rooted teeth were used in this study. All the samples were decoronated at the cementoenamel junction and instrumented in a sequential order from 15 to 50 number k-file. The specimens were randomly divided into five groups containing 20 teeth each. Intracanal medicaments used in this study were Metapex, triple antibiotic paste, Metrogyl DG gel forte (metronidazole gel 1.5% w/w), and curenext gel. For control group following instrumentation, the roots were obturated with laterally compacted gutta-percha with BioRoot RCS. In medicament groups after the period of 14 days, the medicaments were removed. All the four groups were obturated with BioRoot RCS and gutta-percha cones using lateral compaction technique. All the specimens were coated with nail varnish and immersed in 2% methylene blue. Then the specimens were demineralized and diphanized. The cleared teeth were analyzed by means of a stereomicroscope under 10× magnification. All the data were analyzed in SPSS version 18 software (IBM, Chicago, IL, USA). Result: Among all the intracanal medicaments, triple antibiotic paste showed the highest microleakage. When Metpaex and Metrogyl DG gel forte were compared with Curcuma longa, differences were not statistically significant. Conclusion: Among all the intracanal medicaments, triple antibiotic paste showed the highest microleakage and least was Metapex. Clinical significance: Incomplete removal of medicaments prevents the penetration of sealer into the dentinal tubules and interferes with the normal setting reaction, thus affecting the seal of obturating material leading to microleakage and subsequent treatment failure. Hence, while placing an intracanal medicament, it is important to consider its effect on leakage of the root canal system.