Despite the long-term success of press-fit condylar (PFC) knee prostheses, premature failures caused by aggressive rapid osteolysis have been reported. To investigate why patients experience such failures, we reviewed 48 retrieved implants and surrounding tissues together with demographic and radiographic data. Polyethylene degradation was determined from density profiles taken through the retrieved inserts. We compared the histology of tissues around PFC implants with that from around failed implants of similar designs from patients matched to length of implantation, body mass index, and age. The pathologic response in PFC patients showed more widespread, dense, sheet-like cellular infiltrate, whereas in the matched patients, the infiltrate was generally scattered discontinuously. The dominant wear mode of the PFC inserts was severe delamination on the articular surfaces. Wear damage was worse with increased length of implantation and was correlated with oxidative degradation and osteolysis. Degradation and osteolysis were more severe with inserts stored longer and sterilized by gamma radiation in air. These results underscore that degradation and increased shelf life lead to osteolysis and loosening. However, they raise questions concerning the cellular reaction to the debris from PFC implants that could lead to a better general understanding of osteolysis.