Introduction: The aim of this study was to compare the efficacy of irrigation activation regimens and conventional syringe irrigation technique in the removal of modified triple antibiotic paste (mTAP) from root canal walls. Methods: Fifty-six extracted human mandibular premolars were prepared using ProTaper rotary files (Dentsply Maillefer, Ballaigues, Switzerland) up to size F4. The root canals were filled with mTAP medicament, and after 21 days, the roots were randomly assigned to 5 groups (n = 10) according to the irrigation regimens used: conventional syringe irrigation (CI), Self-Adjusting File (SAF; ReDent-Nova, Ra'anana, Israel), EndoVac (Discus Dental, Culver City, CA), EndoActivator (Dentsply, Tulsa, OK), and passive ultrasonic irrigation (PUI). In 3 teeth, mTAP was not removed (positive controls), and another 3 teeth were not filled with mTAP (negative controls). The roots were sectioned, and the amount of remaining medicament at each root half (n = 20) was evaluated at 30x magnification using a 4-grade scoring system. Data were evaluated using the Kruskal-Wallis and Mann-Whitney U tests. Results: There were statistically significant differences among all experimental groups; of which, the CI group was the significantly least efficient in removing mTAP from the root canal (P < .05). At the apical and middle third, the PUI, SAF, EndoVac, and EndoActivator groups removed significantly more mTAP medicament than the CI group (P < .05); however, there were no significant differences between these groups (P > .05). The SAF and PUI showed significantly better performances in removing mTAP from the coronal third (P < .05). Conclusions: The use of irrigation activation regimens significantly improves the removal of mTAP from root canals when compared with CI.