Purpose: To compare the antiemetic efficacy and tolerability of ondansetron plus metopimazine with ondansetron plus metopimazine plus prednisolone during nine cycles of moderately emetogenic chemotherapy. Patients and Methods: A total of 221 women with stage I or II breast cancer and no prior chemotherapy who were scheduled to receive adjuvant chemotherapy with intravenous cyclophosphamide, fluorouracil and methotrexate or cyclophosphamide, epirubicin, and fluorouracil given every 3 weeks were included in a double-blind parallel trial. Patients were randomized to 3 days of oral treatment with ondansetron plus metopimazine, or ondansetron plus metopimazine plus prednisolone. Ondansetron was administered as 8 mg bid, metopimazine as 30 mg qid, and prednisolone as 50 mg qd. Results: In all, 216 patients (97.7%) were assessable for efficacy during a total of 1,462 cycles. In cycle 1, complete protection from emetic episodes/nausea day 1, days 2 through 5, and days 1 through 5 was achieved in 84.4%/51.4%, 82.6%/41.3%, and 79.8%/ 34.9% with ondansetron plus metopimazine and in 84.1%/57.0%, 86.8%/53.8%, and 79.4%/43.0% with ondansetron plus metopimazine plus prednisolone, respectively. In cycle 1, the three-drug combination was superior only in the treatment of nausea on days 2 through 5 (P = .0497). The cumulative emetic protection rate after nine cycles was 0.52 with ondansetron plus metopimazine and 0.75 with ondansetron plus metopimazine plus prednisolone. Side effects were generally few and mild with both treatments. Constipation was the only adverse event significantly more frequent with the three-drug combination (P = .029). Conclusion: Ondansetron plus metopimazine plus prednisolone is highly effective and superior to ondansetron plus metopimazine during nine cycles of moderately emetogenic chemotherapy.