AimThis randomized, prospective, controlled trial assessed the effect of occlusal reduction on post‐treatment endodontic pain and medication intake following root canal treatment of mandibular posterior teeth with symptomatic irreversible pulpitis with sensitivity to percussion treated in two visits.MethodologyThree hundred and eight patients were randomly assigned into two equal groups according to whether occlusal reduction was done or not (n = 154). For all patients, root canal treatment was carried out in two visits without intracanal medication. Patients assessed their pain using the 0–10 numerical rating scale (NRS) 6, 12, 24 and 48 h after the first visit (post‐instrumentation) and 6 and 12 h following root canal filling (post‐obturation). Patients, also, recorded their medication intake (sham or analgesic), post‐instrumentation and post‐obturation; patients initially received a sham capsule, but, if pain persisted, an analgesic was prescribed. Data were analysed using Mann–Whitney U‐test, Friedman’s test, Wilcoxon’s rank test and chi‐square (χ2) test. The relative risk (RR) and its 95% confidence interval (CI) were calculated for binary data.ResultsOcclusal reduction was associated with lower pain intensity than no occlusal reduction at 12 and 24 h post‐instrumentation (P < 0.05). Pain intensity significantly and gradually decreased with both groups at all post‐instrumentation and post‐obturation time‐points compared to preoperative pain (P < 0.05). The RR of moderate‐to‐severe pain was 0.61 (95% CI: 0.41, 0.91) 12 h post‐instrumentation, and the RR of pain incidence, regardless of its level, was 0.75 (95% CI: 0.61, 0.92) 24 h post‐instrumentation. There was no significant difference in medication intake (sham or analgesic) between groups (P > 0.05).ConclusionsOcclusal reduction was effective in reducing the intensity of postoperative pain 12 h and 24 h after root canal instrumentation in the first visit in patients with symptomatic irreversible pulpitis with sensitivity to percussion. Occlusal reduction lowered the risk of moderate‐to‐severe pain by about 40% 12 h post‐instrumentation and the overall risk of pain by 25% 24 h post‐instrumentation; yet, it did not affect medication intake.