A prospective open-label trial was performed to compare the efficacy of dolasetron with that of ondansetron or granisetron (standard therapy) for prevention of nausea and vomiting associated with high-dose chemotherapy with or without total body irradiation followed by hematopoietic stem cell transplantation (HSCT). In a university teaching hospital setting, 62 patients were randomized to receive either dolasetron 100 mg daily or standard doses of ondansetron or granisetron. In addition to objective data such as number of episodes of emesis and quantity of rescue antiemetics required, 100 mm visual analogue scales were used to rate nausea, appetite, and changes in taste. A post-hoc subgroup analysis was performed between groups of patients that were matched for conditioning regimens. Sixty-five percent of the dolasetron-treated patients and 87% of patients in the standard therapy group achieved a major or complete response (P < .05) based on emetic episodes and nausea score. Patients in the standard therapy group used fewer rescue antiemetics and also rated more favorably on selected questions of the visual analogue scale. No differences in safety parameters or adverse effects were reported. At doses prescribed in this study, dolasetron was less effective than granisetron or ondansetron in preventing nausea and vomiting associated with high-dose chemotherapy/total body irradiation followed by HSCT.