The inclusion of casein, either as the acid or sodium salt form, was found to significantly modify the release of the acidic drug diclofenac from hydroxypropylmethycellulose (HPMC, Methocel grades K100LV and K15M)-based matrices. The presence of casein in diclofenac-K100LV matrices increased the drug release rate and rendered the release profile more linear. Furthermore, sodium caseinate appeared to retard the disintegrating tendency of the higher molecular weight HPMC-drug systems, apparently by enhancing the initial gel forming ability of these systems. Surprisingly, dissolution profiles of the salt and acid forms of the drug were similar when co-compressed with sodium caseinate, and addition of HPMC retarded release of both forms of drug to the same extent. Swelling and erosion experiments indicated that the presence of casein decreased the extent of medium uptake (swelling) of the matrices and accelerated the rate of erosion, while not altering the dissolution medium infiltration rate. Phase solubility analysis indicated that the solubility of the drug was also enhanced by sodium caseinate, consistent with complex formation between the drug and casein.