This study was designed to determine whether inflammatory and fibrotic reactions associated with silicone implants are the result of a non-specific foreign body reaction or are unique to silicone. F344 rats were implanted subcutaneously with one of three biomaterials: silicone elastomer; impermeable cellulose filters (carcinogenic positive control); or porous cellulose filters (negative control). After one week and two months, pericapsular tissues were evaluated immunohistochemically for CD4, CD8, CD11b/c antigens, iNOS, DNA strand breaks, apoptosis and proliferation. The acute inflammatory and chronic fibrotic responses were similar between silicone and positive control implants, but both were significantly different from the negative control. Significant increases in cell proliferation and apoptotic cell death were associated with persistent DNA strand breaks in the silicone and positive control implants, but not in negative control implants. Because the cellular responses to the positive control cellulose implants did not differ from those associated with the silicone implants, these results emphasize the importance of appropriate physical controls before cellular responses can be attributed to silicone-specific components. Further, because elevated proliferation and DNA damage are associated with genomic instability in most species, evaluation of human fibrotic capsules surrounding breast implants may be warranted.