Objective:To compare the effect of preoperative administration of an antihistamine, an analgesic, or a placebo on postoperative pain in maxillary molar teeth with symptomatic apical periodontitis. Design: A randomized, controlled trial. Methods: Population: A total of 51 patients with moderate-to-severe maxillary molar tooth pain who have undergone a root canal treatment. Intervention: Preoperative administration of either an antihistamine or an analgesic. Control: Versus placebo Outcomes: Reduction in postoperative pain? The data were analyzed with chi-square, one-way analysis of variance (ANOVA) and least significant difference (LSD) post-hoc tests. Results: At days 1 and 3, preoperative administration of the antihistamine and analgesic resulted in lower pain levels than the placebo. At days 5 and 7, however, while preoperative administration of the antihistamine still resulted in less pain than the placebo, there was no significant difference between the analgesic and placebo (P>0.05). Conclusion: Within the limitations of the present study, the preoperative administration of an antihistamine can be beneficial in reducing the postoperative pain of endodontic treatments.