The aim of this study was to evaluate the potential of poly(methylidene malonate 2.1.2) as a new drug delivery system to the central nervous system. 5-Fluorouracil microspheres were formulated by an emulsion-extraction method, and evaluated on a C6 glioma model. Twenty-seven Sprague-Dawley female rats underwent implantation of various C6 cell concentrations. Magnetic resonance imaging was performed at day 10 to control the setting of the tumor, by using a T2-weighted sequence. At day 12, 18 animals received blank or 5-FU-loaded microspheres, while 9 animals were not implanted and constituted the controls. Thereafter, MRI was performed twice a week to follow the tumor growth. In 12 animals, an alloimmune rejection of the tumor was observed, showing the limitations of the C6 glioma model. When tumor developed, no relationship was observed between the number of C6 cells injected and the tumor volume. 5-FU microsphere efficacy could statistically be demonstrated by significantly improving the median survival of C6 glioma-bearing animals and also by decreasing tumor burden.