A topical pharmaceutical cream containing the active pharmaceutical ingredients (APIs) betamethasone-17-valerate and fusidic acid has been developed for the treatment of inflammatory skin conditions and associated secondary infections. In this work, a novel stability-indicating RP-HPLC method has been developed for the simultaneous quantitation of impurities of both APIs present in this cream. The HPLC column was a 150 mm × 4.6 mm I.D. YMC-Pack Pro C18 column with 3 µm particles. The column-oven temperature was maintained at 40°C and UV detection at 235 nm was used. A gradient programme was employed at a flow rate of 0.7 mL/min. Mobile phase A comprised of a 16:21:21:42 (v/v/v/v) mixture of methanol, 10 g/L phosphoric acid, HPLC grade water and acetonitrile. Mobile phase B comprised of a 24:5:5:66 (v/v/v/v) mixture of methanol, 10 g/L phosphoric acid, HPLC grade water and acetonitrile. The method has been validated according to current International Conference on Harmonisation (ICH) guidelines and applied during formulation development and stability studies. The procedure has been shown to be stability-indicating for the topical cream.