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Rationale and Objectives Technium-99m methylene diphosphonate (99mTc-MDP) bone scintigraphy and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) are useful imaging modalities to detect skeletal metastases. Several other conditions such as infection, fractures, and arthritis can cause false-positive results with either modality. However, PET is felt to be more specific than bone scintigraphy for malignancy. Our objective was to investigate the value of PET scan compared with bone scintigraphy for directing biopsies in patients with suspected metastatic bone lesions. Materials and Methods Retrospective case series of subjects with undergoing skeletal biopsy of suspected metastases detected by 99mTc-MDP scintigraphy or 18F-FDG PET scan. Reference standards were pathologic reports and follow-up for 6 months. The diagnostic test performance measures of true positive (TP), false positive (FP), and positive predictive value (PPV) were calculated for each group. The PPV with 95% confidence intervals (CI) was compared using the Fisher exact test. Results There were a total of 68 subjects. PET-directed skeletal biopsies (n = 39) showed 35 TP, 4 FP, and an 89.7% PPV (95% CI: 75.7–97.1%). Bone scintigraphy directed biopsies (n = 29) had 21 TP, 8 FP, and 72.4 % PPV (95% CI: 52.7–82.7%). The PPV was not significantly different between the groups (P = .10). Conclusion This study supports that PET can be used to effectively direct bone biopsies to confirm metastatic neoplasm and suggests that PET may provide incremental improvement to diagnostic yield over bone scintigraphy. The role of PET compared with bone scintigraphy for directing skeletal biopsies warrants further verification.