Ionically crosslinked microspheres of acrylamide (AAm) grafted poly (vinyl alcohol) (PVA)/sodium alginate (NaAlg) were prepared by crosslinking with FeCl3 and 5-fluorouracil (5-FU), which is an anticancer drug and was successfully encapsulated into the microspheres. The graft copolymer (PVA-g-PAAm) was characterized by using Fourier transform infrared spectroscopy (FTIR) and elemental analysis. The prepared microspheres were characterized by FTIR and scanning electron microscopy (SEM). Microspheres were also characterized by particle diameter, equilibrium swelling values and release profiles. The release studies were carried out at three pH values 1.2, 6.8 and 7.4, respectively, each for 2 h. The effects of preparation conditions as PVA-g-PAAm/NaAlg ratio, drug/polymer ratio, crosslinker concentration and exposure time to FeCl3 on the release of 5-FU were investigated for 6 h at 37 degrees C. The highest 5-FU release was found to be as 99.57% (w/w) at the end of 6 h for PVA-g-PAAm/NaAlg ratio of 1: 4 (w/w), drug/polymer ratio of 1: 8 (w/w), crosslinker concentration of 0.05 M and exposure time of 10 min. The release results were also supported by the swelling measurements of the microspheres. Release kinetics was described by Fickian and non-Fickian approaches.