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Background Context: Growing evidence suggests that obesity is implicated in the progression of heterotopic ossification of the posterior longitudinal ligament of the spine (OPLL), a major cause of myelopathy in Asians. However, it remains unclear whether dysregulation of adipokine production due to fat accumulation contributes to OPLL progression., Purpose: To determine whether adipose-derived biochemical signals are associated with OPLL development or severity., Study Design/setting: A nationwide, multicenter, case-control study., Patient Sample: Patients with symptomatic thoracic OPLL (T-OPLL) who received treatment between June 2017 and March 2021 and 111 controls without OPLL., Outcome Measures: OPLL severity index based on whole-spine computed tomography., Methods: Serum concentrations of adipokines, including leptin (Lep), tumor necrosis factor α (TNFα), and adiponectin (Adpn), as well as the Adpn/Lep ratio-an indicator of adipokine production dysregulation-were compared between the multiple-region OPLL and the single-region OPLL groups. Regression analysis was performed to examine the correlation between adipokine concentrations and OPLL severity index, which was calculated using whole-spine computed tomography images of 77 patients with T-OPLL within 3 years of onset. Using propensity score matching, the adipokine profiles of 59 patients with T-OPLL were compared with those of 59 non-OPLL controls., Results: Patients with multiple-region OPLL exhibited a higher body mass index (BMI), lower serum Adpn/Lep ratio, and higher serum concentration of osteocalcin (OCN) than those with single-region OPLL. The OPLL severity index exhibited a weak positive correlation with BMI and serum Lep levels and a weak negative correlation with the Adpn/Lep ratio. Serum TNFα and OCN concentrations were significantly higher in patients with T-OPLL than in controls with similar age, sex, and BMI., Conclusions: Patients with diffuse OPLL over the entire spine are often metabolically obese with low Adpn/Lep ratios. In patients with OPLL, TNFα and OCN serum concentrations were essentially elevated regardless of obesity, suggesting a potential association with OPLL development. Considering the absence of therapeutic drugs for OPLL, the findings presented herein offer valuable insights that can aid in identifying therapeutic targets and formulating strategies to impede its progression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)