In bone, mechanical stimulation must meet or exceed a mechanical threshold in order to induce an anabolic response. Parathyroid hormone (PTH) is one factor that may reduce the mechanical threshold, increasing bone formation at lower magnitudes of mechanical stimulation. A synergistic interaction between PTH and mechanical stimulation has been noted in both in vivo and in vitro studies. In osteoblasts, both PTH and mechanical stimulation activate mechanosensitive cation channels (MSCC’s), which conduct calcium, an important initial signal in mechanically-induced bone formation. We propose that PTH reduces the mechanical threshold, increasing the response of osteoblastic cells to mechanical stimulation, through activation of MSCC’s. We used fluid forces to mechanically stimulate osteoblast-like MC3T3-E1 cells. The results indicate that 1) PTH significantly enhanced mechanically-induced expression of cyclooxygenase-2 (COX-2), an enzyme involved in mechanically-induced bone formation, 2) PTH reduced the mechanical threshold for intracellular calcium signaling and COX-2 expression, 3) PTH-induced cytoskeletal rearrangement increased the [Ca²⁺]_i response to mechanical stimulation through activation of MSCC’s and voltage-sensitive calcium channels (VSCC’s). Collectively, these studies suggest PTH reduces the mechanical threshold and increase mechanically-induced responses in osteoblast-like cells.