Study Design Retrospective Case control Study. Objectives To analyze the effect of diffuse idiopathic skeletal hyperostosis (DISH) on the occurrence of new thoracolumbar vertebral fragility fractures (VFFs) at different ages. Methods A retrospective analysis of 564 patients, including 189 patients who presented with new-onset thoracolumbar VFFs and 375 patients without spinal fractures, was performed in 4 age groups (50-59 years, 60-69 years, 70-79 years, and 80+ years). DISH was diagnosed based on computed tomography findings, and the Mata score of each disc space level combined with the maximum number of consecutive ossified segments (MNCOS) for each patient was recorded. Data were compared between the fracture and control groups, and odds ratios (ORs) were calculated for each of the 4 age groups using logistic regression. Results Both the crude ORs and the adjusted ORs of DISH for VFFs decreased with age, with statistical significance shown in the 50-59 years group (crude OR = 4.373, P = 0.017; adjusted OR = 7.111, P = 0.009) and the 80+ years group (crude OR = 0.462, P = 0.018; adjusted OR = 0.495, P = 0.045). The Mata scores and the MNCOS were significant risk factors for VFFs ( P < 0.05) in the 50-59 years group, but they were protective factors in the 80+ years group, which was more significant in the T11/12–L5/S1 subsegment. Conclusions The effect of DISH on the occurrence of thoracolumbar VFFs is complex, and in patients above 50 years, it changes from a risk factor to a protective factor with increasing age.