Vascular smooth muscle cell (VSMC) proliferation is a predominant component of primary atherosclerotic plaque formation and restenosis following balloon angioplasty. Angioplasty-dependent activation of a p21ras-dependent response following balloon angioplasty is now well established in models of arterial restenosis. Farnesylation of p21ras is an essential step in this cellular signal transduction pathway. We have previously shown inhibition of farnesyl transferase with FTP III inhibits restenosis following balloon angioplasty (Work et al 2001). As part of our present work on balloon injury of human atherosclerotic arteries in organ culture and culture of non-atherosclerotic veins we studied the effect of FTP III on VSMC proliferation. FTP III concentration-dependently (1-50µM) inhibited smooth muscle cell proliferation as measured by [3H] thymidine incorporation (IC50, 10±1mM. To mimic in-vivo short term delivery we exposed cells to FTP III (25µM) in a time-dependent manner (15mins120mins). Time-dependent exposure to FTP III resulted in 45 ± 5% reduction in smooth muscle cell proliferation. This component of our study of the processes involved in the proliferation of VSMCs derived from human arteries and veins demonstrates a likely role for p21ras-dependent mechanisms. Moreover, a 15min exposure to FTP III had profound effects on VSMC proliferation. This finding may have important implications in the clinical setting as short-term local delivery of a drug may have the potential to limit adverse drug complications.