Purpose: Dolasetron is a 5-HT3 antagonist antiemetic with active oral and intravenous formulations. The effects of this class are enhanced when combined with dexamethasone. This study tested the ability of the combination of oral dolasetron 200 mg and oral dexamethasone 20 mg to prevent acute emesis in cancer patients receiving initial cisplatin at doses ≤ 70 mg/m2. Additionally, patients were randomly assigned to receive a second dosage of the regimen 16 hours later to improve control of acute symptoms. Patients and Methods: A total of 75 patients were entered, with 38 randomized to the two- dose regimen. Thirty-five percent were women and 77% had lung cancer. Results: Overall, the regimen prevented acute vomiting in 76% (95% confidence interval, 65% to 85%), including 74% of 35 patients who received cisplatin at doses ≤ 100 mg/m2. There was no observed difference in emesis prevention between the one-dose (76%) and two-dose (76%) regimens (95% confidence interval for the difference, -20% to 19%). The median time to the onset of emesis was 19 hours for the one-dose regimen and 17 hours for the two-dose regimen in those patients with emesis. Headache occurred in 11% who received one dose and 16% who received two doses. Conclusion: The combination of oral dolasetron 200 mg and dexamethasone 20 mg given only once prevented acute emesis in 76% of patients who received cisplatin ≤ 70 mg/m2. Administration of a second dose of the regimen did not improve the observed prevention rate or delay the time to emesis. This one-dose oral regimen has comparable or better effectiveness than reported results of intravenous combination regimens in preventing cisplatin-induced vomiting and merits further study and use.