The stability of piperacillin sodium plus tazobactam sodium and ranitidine hydrochloride in 0.9% sodium chloride injection during simulated Y-site administration was studied. Triplicate test solutions of piperacillin 40 mg/mL plus tazobactam 5 mg/mL (as the sodium salts) or piperacillin 80 mg/mL plus tazobactam 10 mg/mL (as the sodium salts) were mixed 1:1 with ranitidine 0.5 and 2.0 mg/mL (as the hydrochloride salt). The solutions were stored at 23 degrees C, and samples were removed at zero, one, two, and four hours for measurement of drug concentration by stability-indicating high-performance liquid chromatography. At the time of sampling and before any dilution, each sample was visually inspected for color and precipitation, and pH was determined. At all sampling times, the concentrations of piperacillin, tazobactam, and ranitidine were > 90% of initial concentrations. There were no substantial changes in pH or color. Tazobactam 5 mg/mL (as the sodium salt) and ranitidine 0.5 and 2 mg/mL (as the hydrochloride salt) in 0.9% sodium chloride injection were stable for up to four hours during simulated Y-site administration. Piperacillin 80 mg/mL plus tazobactam 10 mg/mL (as the sodium salts) and ranitidine 0.5 and 2 mg/mL (as the hydrochloride salt) were stable for up to four hours during simulated Y-site administration.