A new simple, sensitive, accurate and precise method has been developed for the simultaneous estimation of Levofloxacin hemihydrate and Cefpodoxime proxetil in pharmaceutical dosage form by RP-HPLC. After optimization good chromatographic separation was achieved by isocratic mode with a mixture of K 2 HPO 4 and methanol pH 8 in the ratio of 40:60 v/v as the mobile phase with YMC C 18 (250 mm × 4.6 mm i.d × 5 µm) column as stationary phase at flow rate of 1mL/min and detection wavelength of 275 nm. The retention time of Levofloxacin hemihydrate and Cefpodoxime proxetil were found to be 2.8 and 3.9 min respectively. The linearity of this method was found in the concentration range of 250 µg/mL to 750 µg/mL for Levofloxacin hemihydrate and 200 µg/mL to 600 µg/mL for Cefpodoxime proxetil. The method was extensively validated according to ICH guidelines Q2B for Linearity, Range, Accuracy, Precision, Specificity and Robustness.