Background Dexamethasone is a potent analgesic and antiemetic. However, the benefit of dexamethasone after TKA is unclear, as is the efficacy in a current multimodal regime. Questions/purposes We determined (1) whether the addition of dexamethasone to a protocol including ramosetron further reduces postoperative emesis compared with ramosetron alone; (2) whether it reduces postoperative pain; and (3) whether it increases the risk for wound complications in a current multimodal regime after TKA. Methods We randomized 269 patients undergoing TKAs to receive dexamethasone (10 mg) 1 hour before surgery and ramosetron immediately after surgery (Dexa-Ra group, n = 135), or ramosetron alone (Ra group, n = 134). We recorded the incidence of postoperative nausea and vomiting (PONV), severity of nausea, incidence of antiemetic requirement, complete response, pain level, and opioid consumption. Patients were assessed 0 to 6, 6 to 24, 24 to 48, and 48 to 72 hours postoperatively. In addition, patients were evaluated for wound complications and periprosthetic joint infections at a minimum of 1 year after surgery. Results The Dexa-Ra group had a lower incidence of PONV during the entire 72-hour evaluation period and experienced less severe nausea for the first 6 hours after TKA, although not between 6 to 72 hours.