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Various therapy modalities have been proposed as standard treatments in management of bone metastases. Radiation therapy remains the standard of care for patients with localized bone pain, but up to 30% of them do not experience notable pain relief. Percutaneous cryoablation is a minimally invasive technique that induces necrosis by alternately freezing and thawing a target tissue. This technique is successfully used to treat a variety of malignant and benign diseases in different sites. 18F-FDG positron emission tomography/computed tomography (18F-FDG PET/CT) is a single technique of imaging that provides in a “single step” both morphological and metabolic features of neoplastic lesions of the bone. The aim of this study was to evaluate the efficacy of the cryosurgical technique on secondary musculoskeletal masses according to semi-quantitative PET analysis and clinical-test evaluation with the visual analogue scale (VAS). We enrolled 20 patients with painful bone lesions (score pain that exceeded 4 on the VAS) that were non-responsive to treatment; one lesion per patient was treated. All patients underwent a PET-CT evaluation before and 8 weeks after cryotherapy; maximum standardized uptake value (SUVmax) was measured before and after treatment for metabolic assessment of response to therapy. After treatment, 18 patients (90%) showed considerable reduction in SUVmax value (>50%) suggestive of response to treatment; only 2 patients did not show meaningful reduction in metabolic activity. Our preliminary study demonstrates that quantitative analysis provided by PET correlates with response to cryoablation therapy as assessed by CT data and clinical VAS evaluation.