The aim of this study was to analyze the clinicopathological features and immunohistochemical expression of p53, MDM2, CDK4, PCNA and Ki67 proteins in 25 head and neck osteosarcomas registered in a single institution. The mean age of the patients was 29 years and the most common site was the mandible (60%). The predominant histological type was the chondroblastic (72%) and 52% of the cases were classified as intermediate-grade of malignancy. The immunohistochemical analysis displayed positivity in 52% of the cases for p53, 24% for MDM2, 84% for CDK4, 92% for PCNA and 88% for Ki-67. The majority of cases were treated with surgery alone or associated with chemotherapy. Five patients developed local recurrences, four had distant metastasis and six had persistent disease after initial treatment. The overall 5-year and 10-year survival rates were 59% and 49%, respectively, and the most important prognostic factors were prior history of radiation exposure and osteoblastic histological type.