Aim of the study: The aim of this study is to evaluate the effect of Prednisolone as Premedication in reduction of post endodontic pain of irreversible pulpitis treated in a single visit using rotary system. Materials and Methods: In this study 40 patients with irrivesrsible pulpitis undergoing root canal therapy were selected. Patients were randomly divided into two groups : Prednisolone group (A) and placebo group (B). Medication was given 30 minutes before start of the treatment. Root canal therapy was accomplished with Revo-S system in a single visit. Evaluation for the incidence of post-endodontic pain, using the visual analog scale approach 6, 12, 24, hours after the treatment was accomplished. Results The results of this study indicated that oral administration of prednisolone in comparison with placebo at 12 and 24 hours periods significantly reduced post treatment endodontic pain by 44% and 38% respectively. Conclusion According to the above findings, oral administration of a single dose of prophylactic prednisolone could significantly reduce post treatment endodontic pain in cases with irreversible pulpitis.