Mechanical effects have been demonstrated to activate periprosthetic osteoclasts and hence to promote bone resorption. However, the periprosthetic mechanical effect on osteoblast function is not clearly understood. The purpose of this study was to explore whether the high pressure on bone caused by a prosthesis affects periprosthetic osteoblast function. We applied static pressure of various magnitudes to SV40-transfected human fetal osteoblast cells, then assayed bioactivities compared to cells cultured without pressure (control). The results showed that osteoblast proliferation, differentiation, apoptosis, necrosis, and mineralization were all sensitive to static pressure, and the effects were magnitude dependent. Low-level static pressure (20 kPa) enhanced osteogenesis. Under 50-100 kPa static pressure, proliferation was inhibited and apoptosis was enhanced, but the cellular phenotype could be maintained. High pressure (250-500 kPa) totally inhibited the bioactivity of the osteoblasts and induced necrosis. Mineralization nodules decreased significantly under 100 kPa pressure, while no nodules could be found under 250 and 500 kPa pressure. RUNX2, COL-1, and BGP mRNA expression was significantly downregulated under 250 and 500 kPa. SOX9 expression was significantly upregulated at 100 kPa but significantly downregulated at 250 and 500 kPa. RANKL/OPG expression was increased under pressure, and the differences were significant at 100 and 500 kPa. These results suggest that periprosthetic high pressure may inhibit osteogenesis and promote osteoclastogenesis. Countermeasures should be developed to improve periprosthetic osteogenesis.