PURPOSE. To assess the biocompatibility of materials for possible use in subretinal prostheses. METHODS. Strips (0.5 x 5 mm; 10-μm thick) of either plain poly(imide) or poly(imide) coated with amorphous aluminum oxide (AAO), amorphous carbon (AC), parylene, poly(vinyl pyrrolidone) (PVP), or poly(ethylene glycol) (PEG) were each implanted into the subretinal space of four Yucatan miniature pigs. Two types of control surgery without implantation were performed in four other animals. Electroretinograms (ERGs) were performed before and after surgery. All animals were euthanatized 3 months after surgery, and histologic slides of the retina were assessed for 15 criteria. Paired, two-tailed Student's t-tests were used for statistical analyses. RESULTS. Across all animals, the mean amplitude of the ERG b-wave did not differ from baseline after 3 months. In implanted animals, the histologic analyses revealed that (1) all the implanted materials produced abnormalities that were significantly greater than in the control subjects; (2) overall, PEG, parylene, and PVP produced less histologic disruption than the other three materials; (3) parylene and PEG did not differ significantly from the control in disturbing retinal anatomy; (4) only PI and AAO produced RPE alterations that were significantly greater than in control subjects; and (5) AAO and PI produced a significantly greater degree of peri-implant cellular responses than did the other materials. CONCLUSIONS. All implants produced some alteration of the retina, but there were clear differences among the materials in the degree to which their presence disturbed the normal anatomy of the retina or RPE or incited tissue reactions around the implant.