A reverse phase-liquid chromatographic method with UV detection at 280 nm is described for simultaneous determination of ceftriaxone sodium and vancomycin hydrochloride. Chromatographic separation of the two drugs was achieved on a Betasil C-1 column using a mobile phase consisting of a binary mixture of acetonitrile and triethylamine buffer adjusted to pH 3.5 ± 0.1 with orthophosphoric acid in a ratio of 20:80. The liquid chromatographic method developed offers symmetric peak shape, good resolution, and reasonable retention time for both drugs. Linearity, accuracy, and precision were found to be acceptable over the concentration ranges 125-750 ppm for ceftriaxone and 62.5-375 ppm for vancomycin. The liquid chromatographic method was successfully applied to the quality control of formulated products, plasma, and cerebrospinal fluid samples containing ceftriaxone and vancomycin.