AbstractObjective(s)We have previously shown that Fas expression inversely correlates with the metastatic potential of osteosarcoma (OS) to the lung. FasL is constitutively expressed in the lung microenvironment and eliminates Fas+ OS cells leaving Fas− cells to form metastases. Absence of FasL in the lung epithelium or blocking the Fas‐signaling pathway interfered with this clearance mechanism allowing Fas+ cells to remain and form lung metastases. We also demonstrated that while the majority of patient OS lung metastases were Fas−, 10–20% of the lesions contained Fas+ cells, suggesting that these cells were not sensitive to FasL‐induced apoptosis. The expression of c‐FLIP, an inhibitor of the Fas pathway, has been associated with tumor development, progression, and resistance to chemotherapy. We therefore evaluated the expression of c‐FLIP in OS patient tumor specimens and human xenograft lung metastases.MethodsOS patient tissues, which included both primary and metastatic lesions, were evaluated for the expression of c‐FLIP. In addition, tumors from human OS xenografts were examined for c‐FLIP expression.Resultsc‐FLIP expression was significantly higher in the lung metastases than in the primary tumors.Conclusion(s)c‐FLIP may play an important role in the metastatic potential of OS to the lung. Inhibition of c‐FLIP may be a future therapeutic target. Pediatr Blood Cancer 2013; 60: 575–579. © 2012 Wiley Periodicals, Inc.