Background: To reduce side-effects of corticosteroid-containing antiemetic regimens, tailoring antiemetic schedules to specific requirements of different patients could be of benefit. We evaluated the possibility to reduce the total dose of corticosteroids when palonosetron, a long-acting second-generation 5-hydroxytryptamine-3 (5-HT3) receptor antagonist, is used. Materials and methods: Double-blind, multicentre, noninferiority study of chemotherapy-naive breast cancer patients receiving 0.25mg palonosetron and 8mg dexamethasone on day 1, randomly assigned to receive placebo (n = 151) or 4mg b.i.d. dexamethasone (n = 149) on days 2 and 3. Primary end point was complete response (CR) rate (no emesis, no rescue medication) in the overall (days 1–5) period. Secondary end points were CR rates in the acute (day 1) and delayed (days 2–5) periods, rates of no emesis and no nausea and impact on daily functioning (Functional Living Index-Emesis). Results: Noninferiority between the two treatments was demonstrated by similar CR rates (P = 0.487) in the overall period. Most parameters showed that palonosetron and dexamethasone on day 1 only offer chemotherapy-induced nausea and vomiting protection similar to multiple-day dexamethasone administration. Conclusion: In patients treated with a single injection of palonosetron on day 1, reducing dexamethasone is an option that is not associated with significant reduction in antiemetic control during the 5-day period or an impact on patient functioning.