Paget's disease of bone (PDB) is characterized by focal increases in bone remodelling. Genome-wide association studies identified a susceptibility locus for PDB tagged by rs5742915 which is located within the PML gene. Here we assessed the candidacy of PML as the predisposing gene for PDB at this locus. We found that the PDB-risk allele of rs5742915 was associated with lower PML expression and PML expression in blood cells from patients with PDB was lower than in controls. The differentiation, survival and resorptive activity of osteoclasts prepared from Pml-/- mice was increased compared to WT. Furthermore, the inhibitory effect of IFN-γ on osteoclast formation from Pml-/- was significantly blunted compared with WT. Bone nodule formation was also increased in osteoblasts from Pml-/- mice as compared with WT. While microCT analysis of trabecular bone showed no differences between Pml-/- mice and WT, bone histomorphometry showed that Pml-/- mice had high bone turnover with increased indices of bone resorption and increased mineral apposition rate. These data indicate that reduced expression of PML predisposes to PDB and identify PML as a novel regulator of bone metabolism.