Imaging-guided percutaneous core needle biopsy (CNB) is the preferred diagnostic method for bone and soft tissue tumors. In less than 1% of cases, complications are clinically significant and include mainly haema-toma and bleeding. We present a case of acute compartment syndrome (ACS) following CNB of the proximal fibula. A 26-year-old female patient was referred to our sarcoma center with a suspicion of giant cell tumor (GCT) of the proximal fibula. The CT-guided CNB under local anesthesia had caused transient severe pain irradiating to the foot, rapidly subsiding after correction of the needle trajectory. The patient was discharged on the same day without residual symptoms. She presented at the emergency department 48 hours later with severe leg pain and swelling. Compartment pressure was elevated. Urgent fasciotomies were performed, revealing muscle edema, without significant haematoma. Postoperatively, paresthesia improved progressively and the patient regained a normal neurologic status within 4 months. Pathologic analysis confirmed the diagnosis of GCT, which was resected after neoadjuvant denosumab therapy. At the 2-year follow up visit, the patient still presented pain at exertion, but had no objective neurological sequela. ACS is not a well-known complication of CNB in the diagnosis of bone tumors. This rare complication might be diagnosed too late, or even missed, due to pre-existing pain, which can sometimes be severe in GCT, and to the usually short post-procedure surveillance in an outpatient procedure.