BACKGROUND AND OBJECTIVE: Pain on injection is still a problem with propofol. The purpose of the study was to compare the effectiveness of diphenhydramine and lidocaine on pain caused by propofol at the site of injection. METHODS: One hundred and eighty ASA I-II adults undergoing elective surgery were randomly assigned into three groups of 60 each. Group I (placebo) received 2 mL normal saline, Group II received 2 mL (40 mg) 2% lidocaine and Group III received 2 mL (20 mg) diphenhydramine intravenously (i.v.) during a 1-min venous occlusion, followed by propofol into a cephalic forearm vein of the antecubital fossa. Pain assessment was made immediately after propofol injection. RESULTS: In the placebo group 25 (41.7%) patients experienced pain during propofol injection as compared to 2 (3.3%) and 3 (5.0%) in the lidocaine and diphenhydramine groups, respectively. The prevalence of pain and pain score were significantly less in both the lidocaine and diphenhydramine groups than in the placebo group (P = 0.00). No difference was found between the diphenhydramine and lidocaine groups (P = 0.60). CONCLUSION: Previous injection of diphenhydramine with venous occlusion can be considered as an alternative to lidocaine for reducing the prevalence of pain caused by injection of propofol into peripheral veins.