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The management of postoperative nausea and vomiting (PONV) remains a persistent problem. Despite the use of prophylactic antiemetics, breakthrough nausea and vomiting still frequently occur. There have been no published studies comparing dolasetron and ondansetron for the treatment of PONV. This was a prospective, randomized, double-blind, active-controlled study in adult outpatient surgery patients. We screened 559 consecutive adult surgery patients, with 92 patients randomized to either ondansetron or dolasetron. The objectives of the study were 1) to determine whether treatment of PONV with ondansetron 4 mg IV or dolasetron 12.5 mg IV would result in better outcomes in patients undergoing day surgery and 2) to compare the cost of drugs used for treating PONV. Thirty-three (70%) of 47 patients given ondansetron required rescue medication, compared with 18 (40%) of 45 patients given dolasetron (P < 0.004). Dolasetron was approximately 40% less expensive than ondansetron, and the costs of the study drug plus rescue antiemetics were 30% less in the dolasetron group than in the ondansetron group. Dolasetron provided greater efficacy for antiemetic treatment because of the need for less rescue therapy. Because of the decreased use of rescue antiemetics and acquisition cost at our hospital, costs in the dolasetron group were less than costs in the ondansetron group.