The objective of this study was to evaluate the physical and chemical stability of undiluted palonosetron hydrochloride 50 micrograms/mL in combination with lorazepam 0.5 mg/mL or midazolam hydrochloride 2 mg/mL in 5% dextrose injection during simulated Y-site administration. Triplicate test samples were prepared by admixing 5 mL of palonosetron hydrochloride with 5 mL of the lorazepam or midazolam hydrochloride admixture. Physical stability was assessed by using a multistep evaluation procedure that included both turbidimetric and particulate measurements as well as visual inspection. Chemical stabililty was assessed by using stability-indicating high-performance liquid chromatographic analytical techniques that determined drug concentrations. Evaluations were performed initially upon mixing and again 1 and 4 hours after mixing. The samples were clear and colorless when viewed in normal fluorescent room light and when viewed with a Tyndall beam. Measured turbidity remained unchanged; particulate content was low and changed little. High-performance liquid chromatographic analysis revealed that palonosetron hydrochloride, lorazepam, and midazolam hydrochloride remained stable throughout the 4-hour test with no drug loss. Palonosetron hydrochloride is physically compatible and chemically stable with lorazepam or midazolam hydrochloride during Y-site administration.