Circulating tissue factor (TF) is an important determinant of coronary thrombosis. Among other cell types, such as monocytes, vascular smooth muscle cells (SMCs) are capable of releasing TF. When studied under static conditions, SMCs do release TF, but this process is slow and, thus, cannot explain the elevated levels of circulating TF, as observed in patients with acute coronary syndromes. The present study demonstrates that cultured human mammary artery SMCs very rapidly (minutes) release active, microparticle-bound TF when exposed to flow conditions. There was a clear log-linear correlation between the shear rate (range 10 s−1 to 1500 s−1) and the procoagulant activity of SMC perfusates. Flow-dependent release of TF was transient (10 minutes) and did not measurably reduce cell surface TF content. Interestingly, a time-dependent (t1/2 30 minutes) re-exposure of releasable TF was detected after a no-flow period. These data demonstrate that SMCs may become a pathophysiologically relevant source of TF that can be rapidly released into the circulation in situations in which endothelial damage occurs and SMCs come into a close contact with the flowing blood.