Biomaterials are becoming increasingly popular for use in spinal cord repair, but few studies have investigated their long-term biocompatibility in central nervous system tissue. In this study, chitosan was compared with two commercial materials, degradable polyglycolide (vicryl and polyglactin 910) and nondegradable expanded poly(tetrafluoroethylene) (Gore-Tex and ePTFE), in terms of host tissue response and biodegradation in the rat spinal cord in two different spinal cord implantation models. In an uninjured model, implants were placed in the spinal cord intrathecal space for up to 6 months. At 1 month, vicryl implants elicited an elevated macrophage/microglia response compared to chitosan and Gore-Tex, which subsided in all groups by 6 months. Fibrous encapsulation was observed for all three materials. At 6 months, the in vivo degradation of vicryl was complete, while Gore-Tex showed no signs of degradation, as assessed by mass loss and SEM. Chitosan implants showed evidence of chain degradation at 6 months as demonstrated by differential hematoxylin and eosin staining; however, this did not result in mass loss. In the second model, implants were placed directly into the spinal cord for up to 12 months. This resulted in increased immune and inflammatory responses but did not alter degradation profiles. The same trends observed for the materials in the intrathecal space were mirrored in the spinal cord tissue. These results demonstrate that chitosan is a relatively inert biomaterial that does not elicit a chronic immune response and is suitable for long-term applications for repair of the spinal cord. © 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part A:, 2011.