This study evaluates the potential use of zein as an excipient in hot-melt extrusion for controlled delivery of diclofenac sodium (DS). Mixtures of zein, polyethylene glycol and drug were hot melt extruded and cut into 2 mm extrudates. Extrudates were characterised using differential scanning calorimetry, X-ray powder diffraction and scanning electron microscopy. The drug in the extrudates was found to be in the non-crystalline state, independent of the drug loading. Moreover, the drug release from extrudates was investigated. The release was directly dependent on the drug loading: a controlled and nearly zero-order release was obtained at the lowest drug loading (12.5% w/w), whereas almost immediate release was achieved at higher drug loadings, i.e. 25% and 37.5%. The release was inversely dependent on the ionic strength of the medium. The influence of digestive enzymes on drug release was also studied. Pancreatin, but not pepsin, was found to have a significant influence on the drug release as well as on the microstructure of zein extrudates. These data therefore support the potential use of zein as excipient in hot melt extrusion for controlled release purposes.