The stability of ranitidine hydrochloride after being mixed with commonly used i.v. beta-lactam antibiotics and administered by simulated Y-site injection was studied. Solutions of ranitidine 1 mg/mL (as the hydrochloride salt), aztreonam 16.7 mg/mL, ceftazidime 20 mg/mL (with sodium carbonate), and piperacillin 30 mg/mL (as the sodium salt) were prepared by reconstitution in i.v. mini-bags. To simulate Y-site injection, 2 mL of ranitidine hydrochloride was mixed with 2 mL of each antibiotic in glass test tubes. These admixtures were prepared in triplicate and stored at room temperature under fluorescent light. Concentrations of each drug in each admixture were determined by stability-indicating high-performance liquid chromatography immediately and after one, two, and four hours. Aztreonam, ceftazidime, and piperacillin each retained more than 95% of the original concentration for at least four hours when mixed 1:1 with ranitidine. Ranitidine retained more than 90% of its original concentration for at least four hours when combined with each of the other drugs. Ranitidine 1 mg/mL (as the hydrochloride salt) and aztreonam 16.7 mg/mL, ceftazidime 20 mg/mL (with sodium carbonate), or piperacillin 30 mg/mL (as the sodium salt) were stable for at least four hours during simulated Y-site administration.