Palonosetron is a potent, selective 5-HT(3) receptor antagonist effective in the prevention of acute and delayed chemotherapy-induced nausea and vomiting. In practice, 5-HT(3) receptor antagonists, including palonosetron, are often coadministered with dexamethasone over approximately 15 minutes, although the approval of palonosetron was based on administration as a 30-second infusion. This open-label, randomized, 2-way crossover trial compared the pharmacokinetics and safety of palonosetron 0.25 mg administered as a 15-minute 50-mL intravenous infusion with a 30-second 5-mL infusion. Aside from an anticipated 40% decrease in maximum plasma concentration after a 15-minute infusion, the pharmacokinetics of palonosetron (including area under the plasma concentration-time curve [AUC], plasma elimination half-life, total body clearance, and apparent volume of distribution at steady state) were similar for both treatments. Both treatments were well tolerated, with no significant changes in vital signs or electrocardiograms. Palonosetron infused over 15 minutes is well tolerated, with an AUC(0-infinity) equivalent to a 30-second infusion.