We have previously shown that phosphodiesterase (PDE) inhibitors induce osteoclast formation by suppressing the degradation of intracellular cAMP. To determine the regulatory roles of PDE inhibitors on PGE2-induced osteoclastogenesis, we investigated the effect of PDE inhibitors on osteoclast formation in the presence of PGE2. We found that IBMX, a nonselective PDE inhibitor, and rolipram, a specific PDE4 inhibitor, decreased PGE2-induced osteoclast formation in cocultures of mouse bone marrow cells and osteoblastic cells. These suppressive effects were observed only when cocultures were treated with PDE inhibitors in the presence of PGE2 at an early stage of differentiation. Northern blot analysis revealed that the PDE4 inhibitor works synergistically with PGE2 to increase the ratio of TRANCE/OPG mRNA in osteoblasts, suggesting that suppression of osteoclast formation by PGE2 and the PDE4 inhibitor is not attributable to their indirect effect on calvarial osteoblasts. We further demonstrated that the PDE4 inhibitor augments the inhibitory effect of PGE2 on osteoclast progenitor cell viability, showing that combined treatment with PGE2 and rolipram suppresses osteoclast formation by directly reducing osteoclast progenitor cell viability.