AimThis prospective, randomized, double-blind clinical trial investigated the impact of diclofenac potassium, prednisolone, and placebo as oral premedication on postendodontic pain and pulpal interleukin (IL)-8 expression in patients with irreversible pulpitis. MethodsThirty-six patients undergoing conventional endodontic treatment were assigned into one of 3 groups (n = 12). Pulpal blood samples were taken after access cavity preparation and stored until they were analyzed using enzyme-linked immunosorbent asssay for quantification of IL-8. Postendodontic pain was scored using the visual analogue scale. Outcome data were statistically analyzed using one-way analysis of variance, Kruskal-Wallis, Friedman's, Dunn's, Chi-square, and Fisher's exact tests and Spearman's correlation coefficient. The significance level (α) was set at 0.05. ResultsApart from preoperative pain scores, all groups had similar baseline characteristics (P > .05). Immediate postendodontic pain scores had a significant difference between all groups (P < .05) where placebo group showed the highest score. There was no significant difference between all groups at 6 and 12 hours postoperatively (P > .05). Furthermore, there was no significant difference in the incidence of postendodontic pain and in mean IL-8 levels between the 3 groups (P > .05). ConclusionsThe only impact the premedications had was on the immediate postendodontic pain intensity, and they had no influence on the later time points, incidence of postendodontic pain or pulpal IL-8 levels.