We explored novel functions of tenascin-C by comparing mouse embryonic fibroblasts (MEFs) proficient or deficient in tenascin-C expression. Transcript profiling analysis identified tissue plasminogen activator (tPA) as the most consistently over-expressed gene in all tenascin-C deficient MEFs. This was confirmed by real-time PCR as well as by protein expression analysis. In agreement with these observations, tenascin-C deficient MEFs had an increased capacity to digest fibrin in situ. Consistently, tenascin-C expression in vivo was found to correlate with fibrin deposition in several diseases associated with tenascin-C overexpression such as fibrosis, asthma and cancer. In conclusion, the present study suggests a new role of tenascin-C as a regulator of the fibrinolytic system.