Objectives: The aim of this prospective randomized clinical trial was to assess the effect of occlusal reduction on post-operative pain after endodontic instrumentation and obturation in patients with symptomatic irreversible pulpitis with symptomatic apical periodontitis in mandibular posterior teeth.Subjects and Methods: Forty four patients with mandibular posterior teeth with symptomatic irreversible pulpitis and symptomatic apical periodontitis without periapical radiolucency underwent two-visit root canal treatment. Patients were randomly assigned into two equal groups of 22 patients each. The occlusal surfaces of teeth assigned to the intervention group were reduced while occlusal contacts were left intact in those assigned to the control group. The root canals were prepared by crown down technique using Revo-S rotary system and 2.6% NaOCl solution and obturated using lateral condensation technique and Resin-based root canal sealer. Pain was assessed preoperatively and 6, 12, 24 and 48 hours following Instrumentation and 6 and 12 hours following root canal obturation. utilizing a modified visual analogue scale (VAS). All demographic data, clinical findings and VAS scores obtained from patients were statistically analyzed. Results: Results showed that, there was a decrease in the mean VAS scores through the follow up periods following root canals instrumentation in the two groups. These results were statistically insignificant between the two groups. There was also no significant difference in the analgesic intake between the two groups.