Background: Piroxicam is nonsteroidal anti-inflammatory drug used for the treatment of inflammatory conditions such as arthritis. Piroxicam belongs to Biopharmaceutical Classification System (BCS) class II, by its low solubility and high permeability through the biological membrane. Objectives:  This study aimed to improve the water solubility of piroxicam by formulating it as nanosuspension using hydroxy propyl methyl cellulose (HPMC E5) as a main stabilizer by the mean of solvent-antisolvent precipitation method. Methods: Different factors were studied and evaluated in an attempt to obtain a monodispersed nanosuspension formula with lower particle size and optimum stability. Seventeen formulas were prepared and characterized for particle size, polydispersity index and drug entrapment efficiency percentage. Results: The results showed that the best formula (F13) has a particle size of (197) nm due to Dynamic Light Scattering Technique measurements. F13 stabilized by the synergistic effect of hydroxy propyl methyl cellulose (HPMC E5) and sodium lauryl sulphate (SLS). Conclusion:The poorly water-soluble piroxicam was successfully formulated as nanosuspension preparation by using an aqueous vehicle, that improved the drug water solubility.