Giant cell tumor of bone is rarely seen in the rib, where it may present as a mediastinal mass. The diagnosis of giant cell tumor of bone is generally straightforward by fine-needle aspiration or needle core biopsy, but sampling problems may lead to confusion with other neoplasms or inflammatory processes. Here, we report a case of giant cell tumor of rib presenting as a mediastinal mass in a 36-year-old man. Because of inadequate sampling and inaccurate clinical information, the tumor was initially mistaken for thymoma. When the mass failed to respond to conventional chemotherapy, additional tissue was obtained and a giant cell tumor was diagnosed. Consequently, definitive therapy was delayed. The case illustrates an important diagnostic pitfall in the biopsy of mediastinal masses.