Obesity is a risk factor for ossification of the posterior longitudinal ligament (OPLL) of the spine, which is characterized by heterotopic bone formation in the posterior longitudinal spinal ligament. Hyperleptinemia is a common feature of obese people and leptin is believed to be an important factor in the pathogenesis of OPLL. However, the association between leptin and bone metabolism and the development of OPLL is not understood fully. The objective of the present study was to determine the association between serum leptin concentration and bone metabolic markers and the extent of heterotopic ossification of the spinal ligament in patients with OPLL. The serum concentrations of leptin, insulin, fructosamine, bone-specific alkaline phosphatase, and carboxyterminal propeptide of type I procollagen, urine deoxypyridinoline levels, and the number of vertebrae with OPLL involvement were measured in 125 (68 males and 57 females) patients with OPLL. The correlation between leptin and these other factors was then examined. Serum leptin and insulin concentrations were increased significantly in OPLL females compared to non-OPLL female controls. In the females with OPLL, serum leptin concentrations corrected for body mass index correlated positively with the number of vertebrae with OPLL involvement. In females, serum leptin levels were significantly higher in patients in whom OPLL extended to the thoracic and/or lumbar spine than in patients in whom OPLL was limited to the cervical spine. Our results suggest that hyperleptinemia, in combination with hyperinsulinemia, may contribute to the development of heterotopic ossification of the spinal ligament in female patients with OPLL.