Parosteal osteosarcoma and low-grade central osteosarcoma are two types of low-grade osteosarcoma that show similar clinical behaviors, histological features, and genetic background (ie, amplified sequences of 12q13-15, including MDM2 and CDK4). Low-grade osteosarcoma is often confused with benign lesions, and ancillary techniques to enhance diagnostic accuracy have been awaited. This study explores the use of MDM2 and CDK4 immunohistochemistry for the histological diagnosis of low-grade osteosarcoma. We studied 23 cases of low-grade osteosarcoma from 21 patients (parosteal osteosarcoma (n=14), low-grade central osteosarcoma (n=9)) and 40 cases of benign histological mimics (myositis ossificans (n=11), fibrous dysplasia (n=14), osteochondroma (n=6), desmoplastic fibroma (n=1), florid reactive periostitis (n=4), Nora's lesion (n=3), and turret exostosis (n=1)). Low-grade osteosarcoma labeled for MDM2 in 16 cases (70%) and for CDK4 in 20 cases (87%). All low-grade osteosarcomas expressed one or both markers (100%), with 13 cases (57%) expressing both. Staining pattern was diffuse in most cases, and the majority expressed moderate or strong intensity for either antibody. MDM2/CDK4 immunostaining was shown irrespective of low-grade osteosarcoma histological subtype. In contrast, only 1 Nora's lesion out of the 40 miscellaneous benign processes showed immunoreactivity for MDM2 or CDK4. The combination of these two markers thus shows 100% sensitivity and 97.5% specificity for the diagnosis of low-grade osteosarcoma. MDM2 and CDK4 immunostains therefore reliably distinguish low-grade osteosarcoma from benign histological mimics, and their combination may serve as a useful adjunct in this difficult differential diagnosis.