To determine the diagnostic performance of image-guided percutaneous core needle biopsy (CNB) in patients presenting with pathologic fractures of the appendicular skeleton. To determine factors associated with non-diagnostic biopsy and identify cases which should be considered for primary open biopsy. A retrospective audit identified 129 consecutive patients presenting with pathological fractures to a specialist orthopaedic oncology unit over a 9 year period. All patients underwent percutaneous CNB using CT (n=98), fluoroscopy (n=15) or US (n=16) guidance. In all cases MRI or CT was available prior to biopsy to assess the presence and degree of extra-osseous tumour mass. The resulting sample was classified as diagnostic (Group 1) or non-diagnostic (Group 2) on histopathological study. Diagnostic performance was evaluated on the basis of the diagnostic yield and accuracy; these were related to the site of the lesion and presence/absence of extra-osseous mass. Of 129 biopsies, 99 (77%) were classified as Group 1 and 30 (23%) as Group 2. The commonest sites of pathological fracture without associated soft tissue component and resulting in a non-diagnostic biopsy were the proximal femur and proximal humerus. The average cross-sectional diameter of lesions in Group 1 was 5.7 x 5.9cm. Of the 30 lesions comprising Group 2, no soft tissue component was identified on pre-biopsy cross-sectional imaging in 27 lesions (90%) whereas the remaining 3 (10%) showed a smaller extra-osseous soft tissue component compared to the lesions in Group 1. Image-guided percutaneous CNB is a reliable method for obtaining a tissue diagnosis in patients presenting with a pathologic fracture of the appendicular skeleton with high accuracy rate. However, those lesions which are purely intra-osseous or have only very small extra-osseous components are likely to be associated with a non-diagnostic biopsy, and should be considered for a primary open procedure.