Introduction: Occlusal reduction is one of several strategies used to prevent or reduce the initiation and progression of post-endodontic pain in cases with symptomatic apical periodontitis, through avoiding further pressure on an already inflamed tooth and further mechanical periapical tissue irritation and inflammation. Objective: The purpose of this randomized clinical study was to evaluate the impact of occlusal reduction on post-instrumentation and post-obturation pain. Subjects and methods: Forty four patients were included in this study. Inclusion criteria were posterior mandibular teeth having symptomatic irreversible pulpitis and symptomatic apical periodontitis. Patients were randomized into two equal groups. In the intervention group the functional and nonfunctional cusps were reduced until absence of contact was confirmed, while in the control group the occlusal surfaces were left intact. Standard endodontic treatment was performed in two visits using rotary nickel titanium files for shaping, 2.5% sodium hypochlorite for cleaning and lateral condensation technique with resin sealer for obturation. Pain was assessed preoperatively, then after 6, 12, 24 and 48 hours following instrumentation, then after 6 and 12 hours following obturation. Visual Analogue Scale (VAS) was used as the primary outcome measure. Patients were given a placebo and ibuprofens 400mg was prescribed to be administrated in case of severe pain and were asked to record number of tablets if any taken. Data were collected and analyzed using Independent t-test, Chi-square and Fisher Exact tests.Results: The incidence of post-operative pain and the mean pain scores were lower in the intervention group than that in the control group at all follow-up periods. The differences between the two groups were significant at 6 and 12 hours following instrumentation and at 12 hours following obturation. There was no significant difference in the incidences of neither placebo nor analgesic intake between the two groups.Conclusions: Occlusal reduction could be a simple effective strategy for controlling post-operative pain following root canal treatment in teeth with symptomatic irreversible pulpitis and symptomatic apical periodontitis.