The implantation of polymer devices in the brain that release neuroactive drugs locally and in a controlled manner is gaining increasing interest. The fates and tissue reactions of poly(epsilon-caprolactone), ethylcellulose, and polystyrene microspheres, prepared by the solvent evaporation method, radiosterilized by gamma-irradiation, and stereotactically implanted in rat brain have been studied by routine staining and immunohistochemistry. During the first few days after implantation, a nonspecific astrocytic brain tissue reaction was observed along with a macrophagous-microglial cell reaction typically found following any damage in the central nervous system, except in the presence of certain foreign body giant cells. Nine months into the experiment, microspheres appeared to be engulfed by histiocytic cells. The microsphere cluster was surrounded by a sheath composed of collagen and astrocytic cells. No necrosis was observed, suggesting the absence of toxicity. In some animals, however, an hydrocephalus developed as a result of obstruction of the medial ventricle by some microspheres.