The bone morphogenetic activities of the primary tumors of 30 patients with osteosarcoma were assayed. This activity was demonstrated as ectopic new bone formation on implantation of freeze-dried fractions of 12 of 30 tumors into athymic nude mice. Pulmonary metastases developed in ten (83%) of the 12 patients with osteosarcomas that produced bone morphogenetic protein (BMP), and bone metastases developed in six (50%) of the patients. The mean period from diagnosis to metastasis was 4.2 months in these patients. In contrast, pulmonary metastases developed in only eight (44%) of the patients with osteosarcomas that did not produce BMP, and bone metastases developed in only two (11%) of these patients. The mean period to metastasis was 12.3 months in these patients. The incidence of metastases in the patients with osteosarcomas producing BMP was significantly higher, and the mean period to metastasis was also significantly shorter than in the other group. The five year survival rates of patients with osteosarcomas that did and did not produce BMP were 33.3% and 54.6%, respectively (P = 0.015, log-rank test). Thus the bone morphogenetic activity of primary osteosarcoma tissue seems to be closely correlated with the prognosis of the patients.