Tenascin-C (TnC) is an extracellular matrix protein that is highly expressed in tumor stroma. In this report, we examined the roles of TnC-mediated cell adhesion in the modulation of chondrosarcoma cell survival. We found that hTnC-mediated adhesion could confer a significant (P<0.05) survival advantage to human chondrosarcoma cell line, JJ012, following serum-deprivation compared with the same cells grown on poly-lysine. This pro-survival signal was due to the activation of the Akt upon adhesion to hTnC. Moreover, hTnC-induced Akt activation was blocked by LY294002 and the expression of dominant-negative Akt. Taken together, these studies support that the TnC-mediated adhesion can promote cell survival through Akt in human chondrosarcoma cells.