OBJECTIVE - Proliferation of vascular smooth muscle cells (VSMCs) contributes to restenosis after coronary intervention. We have shown previously that increased expression of plasminogen activator inhibitor type 1 (PAI-1) limits VSMC apoptosis. Because apoptosis and proliferation appear to be linked, we sought to determine whether increased PAI-1 would affect VSMC proliferation. METHODS AND RESULTS - VSMCs were explanted from control and transgenic mice (SM22-PAI) in which VSMC expression of PAI-1 was increased. Increased growth of SM22-PAI-VSMCs (2.3±0.4-fold) reflected, at least partially, increased proliferation. Greater expression of FLICE-like inhibitory protein (FLIP; 2.7-fold) and its cleaved active form were seen in SM22-PAI-VSMCs. The balance between caspase-8 and FLIP favored proliferation in SM22-PAI-VSMCs. Increased expression of NF-κB and activation of extracellular signal-regulated kinase (ERK) were demonstrated in SM22-PAI-VSMCs (fold=NF-κB=2.2±0. 1, fold=phosphorylated-ERK=1.6±0.1). Results were confirmed when expression of PAI-1 was increased by transfection. Inhibition of NF-κB and ERK attenuated proliferation in SM22-PAI-VSMCs. Increased expression of PAI-1 promoted proliferation when VSMCs were exposed to tumor necrosis factor (TNF). CONCLUSIONS - Increased expression of PAI-1 is associated with greater activity of FLIP that promotes VSMC proliferation through NF-κB and ERK. Thus, when vascular wall expression of PAI-1 is increased, restenosis after coronary intervention is likely to be potentiated by greater proliferation of VSMC and resistance to apoptosis. © 2006 American Heart Association, Inc.