The unique design characteristics of an uncemented femoral component were used to study differences in the periprosthetic membranes in the presence and absence of osteolysis. A component (Omniflex, Osteonics, Allendale, NJ) that has a large midportion of the stem that does not contact bone was studied. A membrane forms, even in the absence of bone resorption, in Gruen zones 3 and 5 of this component. Analysis of this membrane showed noninflammatory fibrous tissue, no or minimal particulate debris, and few macrophages. In contrast, analysis of membranes from osteolytic regions around the same prosthesis demonstrated typical inflammatory characteristics. Collagenase, gelatinase, and stromelysin expression was high in osteolytic membranes but was low in tissues from noninflammatory regions without osteolysis. The data suggest a sequence of events in periprosthetic membrane formation. A noninflammatory membrane initially forms between the bone and the prosthesis. This membrane is transformed into an inflammatory membrane by the influx of particulate debris. Matrix metalloproteinases are selectively expressed in regions of osteolysis, implicating these enzymes in periprosthetic bone loss and suggesting a possible level for pharmaceutical intervention to prevent or treat osteolysis. Formation of the noninflammatory membrane around the distal part of the prosthesis of this or similar designs in the absence of bone resorption implies that these tissue samples could serve as useful negative control tissues to identify factors present in osteolytic periprosthetic membranes.