The compatibility and stability of esmolol hydrochloride in admixtures during simulated Y-site injection of morphine sulfate or fentanyl citrate was studied. One milliliter of either morphine sulfate (15 mg/mL) or fentanyl citrate (0.05 mg/mL) was injected into a running infusion of esmolol hydrochloride (10 mg/mL) in 5% dextrose and 0.9% sodium chloride injection, and the solution was visually observed for changes. To determine the stability of the drugs during Y-site injection, esmolol hydrochloride 4 mL (1000 mg) in 5% dextrose and 0.9% sodium chloride injection was combined with 100 mL of either morphine sulfate 15 mg/mL or fentanyl citrate 0.05 mg/mL to simulate concentrations of the drugs that might be expected during Y-site injection. The admixtures were stored at ambient room temperature under normal light, and drug concentrations were determined using high-performance liquid chromatography at time zero and at two, four, and eight hours. Admixtures were also tested for pH and observed for visual changes. No immediate changes were observed in any of the admixtures, and the concentrations of the drugs varied by less than 4% throughout the study period. No precipitate or color changes were noted during Y-site injection of either drug into the running esmolol infusion. Under all of the conditions studied, esmolol hydrochloride in 5% dextrose and 0.9% sodium chloride injection is compatible with morphine sulfate or fentanyl citrate.