A simple stability indicating RP-HPLC method has been developed for the simultaneous determination of Cefixime in combination with Acetylcysteine using ODS C18 column (250 × 4.6 mm, 5 μm) with UV detection at 274 nm. The mobile phase consisting of 0.1% Ortho Phosphoric Acid (OPA) and acetonitrile in a ratio of 58:42, v/v and at a flow rate of 1.0 mL/min. The method was linear over the concentration range for Cefixime 50-375 μg/mL and for Acetylcysteine 75-400 μg/mL. The retention times for Cefixime and Acetylcysteine were found to be 2.018 min and 5.141 min respectively. The average percentage recoveries of active pharmaceutical ingredient (API) Cefixime and Acetylcysteine were found to be in the range of 99.23% and 100.13% respectively. The method was validated and was successfully employed for the routine quantitative analysis of pharmaceutical formulations containing Cefixime and Acetylcysteine in combined tablet dosage form.