Purpose <p>Vertebral compression fractures (VCF) account for a significant health burden worldwide. They are caused by osteoporosis or pathologic lesions resulting from primary or secondary malignant processes. These fractures are often treated with kyphoplasty, an effective minimally-invasive procedure intended to return structure to vertebrae. However, the risk of complications following kyphoplasty in pathologic fractures compared to typical fractures has not been quantitatively assessed.</p> Methods <p>Data was collected from a large national database. After propensity matching, cohorts of 6,027 patients with pathologic VCFs and 6,027 patients with nonpathologic VCFs who underwent kyphoplasty were created. The rates of pulmonary embolisms (PE), vertebral osteomyelitis, and spinal stenosis were recorded, and relative risk and 95% confidence intervals were calculated.</p> Results <p>Of the 6,027 patients in our pathologic cohort, 243 (3.5%) experienced PE, in the 30 days following kyphoplasty; 38 (0.6%) vertebral osteomyelitis, and 711 (11.8%) spinal stenosis in the 90 days following kyphoplasty. Of the 6,027 in the nonpathologic cohort, 80 (1.2%) experienced PE in the 30 days following kyphoplasty; 35 (0.5%) vertebral osteomyelitis, and 700 (11.6%) spinal stenosis in the 90 days following kyphoplasty. This was a significant difference in the frequency of PE (<i>p</i> &lt; 0.0001) between cohorts but no significant difference in vertebral osteomyelitis (<i>p</i> = 0.725) or spinal stenosis (<i>p</i> = 0.75).</p> Conclusion <p>Patients undergoing kyphoplasty for pathologic vertebral compression fractures have an increased risk of PE but not osteomyelitis or spinal stenosis. Closer monitoring for PE is warranted in this population, whereas standard postoperative protocols remain appropriate for infection surveillance.</p>