Background/Aims: Differential diagnosis between aggressive osteoblastoma and low grade osteosarcoma may be very difficult or even impossible on a small biopsy. This study was designed to assess the usefulness of immunoexpression of COX-2 and osteocalcin in the differential diagnosis of the two tumour types. Methods: Immunostaining of COX 2 and osteocalcin were studied in 9 osteoblastomas and 30 osteosarcomas. Results: All osteoblastomas and 11/20 (55%) high-grade osteosarcomas showed COX-2 immunoreactivity. All low grade osteosarcomas were COX-2 negative. COX-2 was significantly higher (p<0.002) in osteoblastomas 9/9 (100%) than in osteosarcomas 13/30 (43%) and in aggressive osteoblastomas versus low grade osteosarcomas (p<0.01). Osteocalcin was found in tumour cells of all osteosarcomas and osteoblastomas and in the osteoid matrix of 84% of osteosarcomas and 78% of osteoblastomas. Strong osteocalcin was significantly higher (p<0.02) in osteoblastomas (78%) than in osteosarcomas (27%). Conclusion: COX-2 is a valuable marker in distinction between osteosarcoma and osteoblastoma. Negative COX-2 could confirm the diagnosis of low grade osteosarcoma versus aggressive osteoblastoma. Intensity and distribution of osteocalcin may indicate the degree of osteoblastic differentiation.