Biochemical, histologic, and immunohistochemical analyses were performed on 34 interface membranes obtained from 33 patients during revision total knee arthroplasty. The membranes had surrounded components of cementless(n = 11) and cemented (n = 23) knee prostheses that were aseptically loose. None of these implant failures was caused by catastrophic polyethylene erosion leading to metal-to-metal contact. The histologic findings were similar in the membranes from cemented and cementless knee components: small polyethylene debris within macrophages and large birefringent polyethylene debris within foreign-body giant cells. Metallic debris was seen in membranes from both groups, but cemented membranes had more polymethylmethacrylate particles and more hyalinization. Intracytoplasmic asteroid bodies were observed in several foreign-body giant cells in both types of membranes. No significant differences were found between the two groups in levels of collagenase, prostaglandin E2 (PGE2), interleukin-1 (IL-1), interleukin-6 (IL-6), or tumor necrosis factor-alpha (TNF-α), nor in the population of inflammatory cells stained with IL-1, IL-6, and TNF-α antibodies. Membranes that had surrounded components with radiographic evidence of diffuse or localized periprosthetic bone loss released significantly more collagenase, IL-1, IL-6, and TNF than did membranes from components without bone loss. These two groups, however, did not have significantly different PGE2 levels. These findings suggest that polyethylene and metal debris may play a role in macrophage activation and the release of mediators of bone resorption in the membranes surrounding failed cemented and cementless total knee implants.