Aim: Clinical evaluation and comparison of the effect of 2% chlorhexidine gel and triple antibiotic paste with calcium hydroxide on incidence of interappointment flare-up in diabetic patients. Materials and Methods: Thirty-six diabetes mellitus patients seeking endodontic treatment were assigned to three groups: Group I - calcium hydroxide paste, Group II - triple antibiotic paste, and Group III - 2% chlorhexidine gel. Access opening and chemomechanical preparation was done followed by the placement of intracanal medicaments. Samples were then assessed for the incidence of intra-appointment flare-up at 1, 2, 3, 7, and 14 days using verbal rating scale. Obtained scores were statistically analyzed using one-way ANOVA test and Tukey's post hoc test. Results: Total incidence of interappointment flare-up was found to be 13%. For all the groups, statistically significant difference (P Conclusion: Both triple antibiotic paste and 2% chlorhexidine gel were significantly effective for minimizing the interappointment flare-up and postoperative symptoms in diabetic patients. 2% chlorhexidine gel found to be more effective clinically, as compared to other experimental groups.