Poly(2-hydroxyethyl methacrylate-co-acrylamide) hydrogels crosslinked with ethylen glycol dimethacrylate were used as devices for the in-vivo drug release of 5-fluorouracil (5-FU). Drug-loaded hydrogels were subcutaneously implanted in the back of Wistar rats. All hydrogel discs reached an equilibrium swelling degree, which was slightly larger than that determined in-vitro. After 30 days of implantation, the hydrogel discs were transparent, and without fracture or apparent degradation. In addition, a fibrous capsule was not detected around the hydrogels that had greater hydration degrees. Release of 5-FU from these hydrogels allows the drug to remain in the plasma from 1 to 5 days, in spite of its short plasma half-life (15 min). This was an improvement of up to 98-times compared with the intraperitoneal drug administration. Administration of 5-FU by implantation of 2-hydroxyethylmethacrylate-co-acrylamide copolymeric hydrogels seems to be a good candidate for 5-FU therapy, since the drug released results in a therapeutically suitable plasma concentration of 5-FU for an extended period of time, despite the short half-life of the drug.