Osteosarcoma is the most frequent primary malignant bone tumor in children and adolescents with a high propensity for lung metastasis, the major cause of disease-related death. Reliable outcome-predictive markers and targets for osteosarcoma metastasis-suppressing drugs are urgently needed for more effective treatment of metastasizing osteosarcoma with a current mean 5-year survival rate of approximatly 20%. This study investigated the prognostic value and the biological relevance of the extracellular matrix-associated growth factor Cyr61 of the CCN family of secreted proteins in osteosarcoma and metastasis. The prognostic value of Cyr61 was assessed with Kaplan-Meier analyses based on Cyr61 immunostaining of a tissue microarray of osteosarcoma biopsies collected from 60 patients with local or metastatic disease. Effects of Cyr61 overexpression on intratibial tumor growth and lung metastasis of the low metastatic human SaOS-2 osteosarcoma cell line were examined in SCID mice. Cyr61 provoked signaling was studied in vitro in non-manipulated SaOS-2 cells. Cyr61 immunostaining of osteosarcoma tissue cores correlated significantly (P=0.02) with poor patient survival. Mice intratibially injected with Cyr61 overexpressing SaOS-2 cells showed faster tumor growth and an increase in number and outgrowth of lung metastases and consequently significantly (P=0.0018) shorter survival than mice injected with control SaOS-2 cells. Cyr61-evoked PI-3K/Akt/GSK3b signaling in SaOS-2 cells resulted in a sub-cellular redistribution of the cell cycle inhibitor p21(Cip1/WAF1) . Cyr61 has considerable potential as a novel marker for poor prognosis in osteosarcoma and is an attractive target for primary tumor and metastases suppressing drugs. © 2011 American Society for Bone and Mineral Research.