Ethosomes are the novel lipid carriers composed of ethanol, phospholipids and water.These are soft, malleable vesicles tailored for enhanced delivery of active agents. They are the slight modification of well established drug carrier liposome.The present investigation was to design the ethosomes containing Betamethasone valerate using different concentration of ethanol and phospholipid (Soya Lecithin). It is a BCS class II drug (low solubility and high permeability). The aim of this work is to improve the bioavailability of Betamethasone byformulating ethosomes. Ethosomes were prepared according to aBox-behnken design. The selected variables were the amount of soya lecithin, ethanol and stirring speed. In total fifteen batches were prepared. The prepared formulations were characterized for their drug content, particle size, zeta potential and in-vitro permeation study. The optimized formulation had a size of 124.2 nm, zeta potential (−17.0), and entrapment efficiency of 88.5% and showed a sustained release pattern over 12 hrs. Micrographs of the transmission electron microscope confirmed the nanostructure of the optimized formulation.