Crosslinked hydrogels with well-defined chemical structures and characteristics were prepared through the reaction between diepoxy-terminated poly(ethylene glycol)s of various molecular weights and aliphatic polyamines of different hydrocarbon chain length and functionalities, and the influence of some network parameters (molecular weight between crosslinking points, crosslinking degree, hydrophobic character) upon the absorption and release of drugs of different capacity to interact with the polymer chains was comparatively investigated. Diclofenac sodium (DCFNa) and 5-fluorouracil (5FU) were used as model drugs, based on their dissimilar hydrophobic character and ability of DCFNa to form crown ether-like complexes with PEG chains through the sodium cation. The experiments showed that the most important interactions occurring in these systems were mainly the hydrophobic ones and to a lesser extent the complexation of the Na(+) ion by the PEG chains. Both of them were in favor of DCFNa, resulting in a larger incorporation and a slower release of this one in comparison with 5FU. For both drugs, loading was larger for hydrogels with shorter PEG chains and/or crosslinked with amines with longer hydrocarbon chain or higher functionality. Drug release tests showed a lower rate for stronger drug-network interactions in agreement with the absorption experiments.