Acetate (Ac-), aminoethyl (AE-), and carboxymethyl (CM-) high amylose starch cross-linked 6 (HASCL-6) derivatives were previously shown to control the release of drugs over 20 h from monolithic tablets highly loaded (up to 60% drug). This report describes the swelling characteristics, which allow a better understanding of the mechanisms involved in the control of the drug release from the said polymeric matrices. The tablet swelling of HASCL-6, Ac-HASCL-6, and AE-HASCL-6 was found to not be affected by the ionic strength and by the pH between 1.2 (gastric) and 7 (intestinal), whereas the swelling of CM-HASCL-6 was shown to depend on both ionic strength and pH of the release medium. For all the studied polymers the drug loading did not change the equilibrium swelling ratio but affected the initial swelling velocity, seemingly due to the competition between drug and polymer for water uptake, a phenomenon probably influenced by the loading and the drug solubility. It was also shown that the increase of ionic strength would slightly increase the drug release time probably by decreasing the amount of free water still available to solubilize the drug present into the matrix.