Piroxicam is a nonsteroidal anti-inflammatory drug used to treat arthritis and other inflammatory conditions (1). Crystalline piroxicam is polymorphic and exists in various crystalline forms designated as form I, form II, form III, and monohydrate form. Form I is also named β, cubic form, and form A, meanwhile form II is termed α, α1, α2, needle form, and form B (2,3). Form III is thermally unstable and can be converted to form II and form I, respectively (2). Additionally, the monohydrate form can dehydrate to form I (4). Generally, the polymorphic form of a drug can transform to a more stable form during storage and manufacturing process, such as drying, milling, and compaction (5,6). The extent of conversion is dependent on the relative stability of the polymorphs and kinetic factors. Moreover, these crystal structures can have different chemical and physical properties (6). Nevertheless, the crucial properties are dissolution, bioavailability and subsequently therapeutic effectiveness of the drugs. Typically, the metastable or thermodynamically instable forms exhibit best solubility and bioavailability (2,6). However, the most stable polymorphic form is often selected for pharmaceutical development based on the minimal potential for conversion to other polymorphic forms and on its greater chemical stability. However, in some cases, such as ranitidine HCl, more than one polymorph are used in commercial formulation (7). A number of techniques have been used to determine polymorphs including thermal analysis (DSC) (8), X-ray powder diffraction (XRD) (9), near-infrared spectroscopy (NIR) (10), Fourier transform infrared (FTIR) spectroscopy, attenuated total reflectance (ATR) FTIR (11), diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) (9,12,13), and Raman spectroscopy (14), Different techniques are appropriate for analysis of polymorphs of particular drugs. DRIFTS has been commonly used to determine various polymorphs. This method has advantages over conventional FTIR in terms of easier and more rapid sample preparation and no crystal structure changes during sample preparation which can possibly occur in FTIR. Furthermore, these analytical approaches have been effectively used in combination with various chemometric methods including partial least square (PLS)(12,13) and artificial neural network(15) for quantification of polymorphs. Polymorphic conversion is a major concern of the pharmaceutical industry. Therefore, it is essential to characterize and quantify polymorphic forms of drugs. According to Ghan and Lalla (16), piroxicam form II can transform to form I by compression force. At present, piroxicam forms I and II are commercially available in various countries. However, form I, which is more stable than form II, is more extensively used to manufacture commercial capsules and tablets. The objective of this study is to investigate the use of DRIFTS and PLS to determine piroxicam forms I and II in binary mixtures of these two polymorphs alone and in the presence of pharmaceutical excipients. In addition, this is the first study that quantifies the mixture of piroxicam polymorphs.