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Background Aprepitant blocks the emetic effects of substance P. Scopolamine antagonizes muscarinic type 1 and histamine type 1 receptors. This study compares monotherapy and multimodal therapy by looking at complete response, nausea, vomiting, and rescue medication in patients at high risk for postoperative nausea and vomiting (PONV) treated with oral aprepitant with or without scopolamine. Methods We enrolled 120 patients in this randomized, double-blind trial. Inclusion criteria were: >18 yr old, ASA I–III, two or more Apfel four-point risk factors, undergoing an elective surgical procedure with a high risk of PONV expected to last at least 60 min. The primary outcome variable was complete response, that is, no emesis and no rescue therapy from 0 to 24 h. The outcomes measured included the incidences of nausea, vomiting, their composite, and the need for rescue medication. Results The aprepitant alone and aprepitant with scopolamine did not differ in complete responses (63% vs 57%, P=0.57) or net clinical benefit (26% vs 19%, P=0.38). The number who did not experience PONV and who used rescue medication did not differ. The incidence of PONV in the post-anaesthesia care unit did not differ nor did the use of rescue medications. Conclusions This trial evaluating the effectiveness of aprepitant alone and in combination with scopolamine showed no difference between treatment groups. The primary objective, complete response, and secondary objectives, incidences of nausea, vomiting, their composite, and the need for rescue medication, all showed no statistical difference. [ABSTRACT FROM AUTHOR]