High amylose corn, waxy corn, and potato starches were crosslinked (XL) to an optimal degree and then substituted with carboxymethyl (CM) and aminoethyl (AE) groups, and their drug release properties, swelling power, and potential interactions with drugs were investigated. Propranolol hydrochloride, sodium diclofenac and acetaminophen were used as model drugs. High amylose starch required a higher XL degree to achieve good sustained release properties, whereas waxy corn required the least XL. Drug release was more governed by the matrix characteristics than by drug properties, and XL-CM high amylose corn starch displayed a nearly constant drug release for all three drugs tested. Swelling power correlated well with sustained release properties with the better matrices swelling to greater extents. There was a potential interaction between XL-AE-starches and diclofenac as indicated by differential scanning calorimetry. Starches from different sources require different types and degrees of modifications to achieve satisfactory sustained release. (C) 2010 Wiley Periodicals, Inc. J Appl Polym Sci 117: 1558-1565, 2010