The etiology of aseptic loosening of prosthetic joint replacement components is unclear. Implant materials have been considered biologically inert, but recently studies indicate that inflammatory reactions directed against the implanted materials may contribute to aseptic loosening. Data suggesting a progression from a simple inflammatory reaction to complex immune responses against the biomaterials are reviewed. The cellular responses to particles of polymethylmethacrylate, ultrahigh molecular weight polyethylene, and alloys of cobalt-chromium and titanium were assayed in vitro to determine cell proliferation in patients with underlying diagnoses of osteoarthrosis, rheumatoid arthritis, and avascular necrosis who had joint replacement. Control populations were provided by patients with similar diagnoses who were preoperative surgical candidates. The underlying diagnoses did not seem to influence responses to particle stimulation. Elevated responses to both acrylic and cobalt-chromium were observed in patients with aseptically loosened prostheses. These findings suggest that the development of a cellular response to particulate debris may be significant in the pathogenesis of aseptic loosening.