Aim: eliminating or reducing pain following endodontic treatment is of great importance. The aim of this study is to compare the effects of Tramadol, Novafen and Naproxen on post-operative pain following instrumentation of root canals in teeth with irreversible pulpitis. Sample size: one hundred patients considering the inclusion and exclusion criteria were selected. Intervention and outcome: The effect of Tramadol, Novafen and Naproxen on post-operative pain following instrumentation of root canals in teeth with irreversible pulpitis was evaluated.