The mechanisms leading to aseptic loosening of a total hip replacement are not fully understood. A fibrous tissue interface can be present around the implant. Hypothetically, component micromovements can compress this interface and cause increased fluid pressure according to biphasic models. We tested the hypothesis that compression of a fibrous membrane with or without the presence of high-density polyethylene particles leads to bone degradation. A titanium implant was inserted in forty-five rabbit tibiae, and, after osseous integration was achieved, a fibrous tissue interface was generated. The animals were randomized to undergo a sham operation, treatment with compression of the fibrous membrane, treatment with high-density polyethylene particles, or treatment with both compression and particles. Morphometric analysis of the surrounding bone was performed on cryostat sections after Giemsa staining and staining of tartrate-resistant acid phosphatase activity. Forty specimens were available for analysis; five tibiae with an infection were excluded. After nine weeks, the controls showed vital bone, whereas the specimens treated with compression showed necrosis of bone and replacement of bone by cartilage in a discontinuous layer (p < 0.05 for both) but not fibrous tissue. Treatment with high-density polyethylene particles caused replacement of bone by fibrous tissue (p < 0.05) but not necrosis or cartilage formation. Compression combined with the presence of high-density polyethylene particles caused bone necrosis and loss of bone with replacement by cartilage and fibrous tissue (p < 0.05). In this in vivo study in rabbits, fibrous membrane compression led to bone necrosis and cartilage formation, possibly because of fluid pressure or fluid flow, whereas the presence of high-density polyethylene particles led to the loss of bone with replacement of bone by fibrous tissue. Cartilage formation may be a protective response to fluid pressure and/or fluid flow. Fibrous membrane compression may play an important role in the early stages of loosening of a total hip replacement.