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Background: The aim of this study was to identify the rate of unsuspected malignancy in vertebral compression fractures (VCFs) treated with percutaneous vertebral augmentation procedures (PVAPs). Methods: From 2004–2015, 410 patients with VCFs underwent PVAPs with biopsy in a single tertiary hospital. All patients had preoperative magnetic resonance imaging (MRI) read by consultant radiologists and reviewed by the performing surgeon prior to PVAPs. All procedures were performed by fellowship-trained spine surgeons. A patient was considered to have an unsuspected malignancy if preoperative MRI was negative for malignancy but histology from the operative biopsy was positive. Results: A total of 44 of 45 patients (97.8%) were identified to have malignancy on preoperative MRI. One patient had a negative MRI but positive biopsy (myeloma). This patient also had a positive myeloma panel. A total of 41 of 44 patients with suspicious MRI preoperatively had a history of malignancy with histology consistent with metastatic spread from the known primary. Two patients had a new diagnosis of malignancy (1 breast carcinoma, 1 metastatic cancer likely of breast or gastrointestinal origin). Younger patients were more likely to have a VCF due to malignancy (odds ratio, 28.33 in age Conclusions: Almost 98% of patients with malignancy (44 of 45 patients) could be successfully identified with a preoperative MRI. The addition of a myeloma panel to MRI identified all patients with malignancies prior to PVAP in our study. We recommend MRI and myeloma panel for all patients with VCFs to be treated with PVAPs. For patients who undergo a PVAP, routine biopsy should be performed.