Giant cell tumor of bone (GCT) is a benign locally aggressive neoplasm composed of mononuclear cells admixed with innumerable osteoclast-type giant cells. H3F3A gene mutations producing mutant histone protein product H3.3 have been identified in 96% of GCT; mutant H3.3 is reliably demonstrated by immunohistochemistry. GCT may contain woven bone and rarely, neoplastic cartilage nodules which causes diagnostic challenges with aggressive neoplasms such as osteosarcoma. We describe the features of GCT with cartilage matrix and report the next-generation sequencing findings in a subset of tumors. Seventeen cases of GCT with cartilage matrix form the cohort: 7 males and 10 females, 13 to 55 (mean: 25) years old. Tumors involved the fibula (6), femur (6), and patella, tibia, humerus, S1, and scapula (1 case each). Tumors were radiolucent, circumscribed, lytic, and expansile. All contained classic GCT, foci of cartilage matrix, and trabeculae of woven bone. Immunohistochemistry showed diffuse staining for H3.3 in 9/9 cases and 1 case was positive for S100 and SOX9 in the cartilage areas. Next-generation sequencing showed a mutation in the H3F3A gene in 6/6 cases. On follow-up, 2 patients who underwent resection showed no disease after 12, and 7 months, respectively. Three patients had recurrences 10, 12, and 27 months after curettage; there were no metastases. GCT with cartilage matrix is uncommon. The cartilage matrix is associated with woven bone suggesting the neoplastic cells may differentiate into chondrocyte-like and osteoblast-like cells. Recognition of this neoplasm is important to prevent misdiagnosis and overtreatment of affected patients.