Giant cell tumor of the bone (GCTB) is a common primary benign tumor, but in some cases, it behaves aggressively, resulting in tumor recurrence. The standard treatment for GCT is thorough curettage with adjuvant treatment such as phenol, liquid nitrogen, high-speed burr, or methylmethacrylate cement. This article presents the case of a 30-year-old male with GCT of the right distal femur, which demonstrated a complete necrosis of GCTB. Interestingly, the specimen also showed adipocytic lineage, and strong expression of apoptotic markers by [terminal deoxynucleotidyltransferase dUTP nick-end labelling (TUNEL) and caspase-3] and peroxisome proliferator-activated receptor gamma (PPAR gamma). To the Authors' knowledge, this is the first reported case of complete necrosis of GCTB concurrent with adipocytic lineage and high expression of PPAR gamma. PPAR gamma is a master regulator of fat differentiation. PPAR gamma possesses antitumor activity through suppression of tumor proliferation and invasion and induction of differentiation and apoptosis. Although we could not conclude on the exact cause of complete necrosis and high expression of PPAR gamma in this case, we focused on the medical history, where this patient took zaltoprofen (240 mg/day) for four weeks before the biopsy to alleviate his pain. Zaltoprofen is a propionic-acid derivative non-steroidal anti-inflammatory drug, and it is reported to act as a direct ligand for PPAR gamma. We speculated that one of the possible mechanisms of PPAR gamma activation in this case was induction by zaltoprofen, at least in part. Although further analysis using cultured tumor cells with ligands specific to the receptor is necessary, PPAR gamma may be a novel therapeutic target in GCTB.