Anti-inflammatory properties of transforming growth factor-β1 (TGF-β1) may account for its protective role against atherosclerotic plaque rupture. The transcription factor Nrf2 mediates induction of cytoprotective genes such as heme oxygenase-1 (HO-1) via activation of antioxidant response elements (ARE). HO-1 catabolises the pro-oxidant heme to generate the vasodilator carbon monoxide and antioxidants biliverdin and bilirubin. Macrophage migration inhibitory factor (MIF) has multiple functions in inflammatory processes, exhibits catalytic thiol-protein oxidoreductase activity and plays a role in redox homeostasis. The present study investigates whether TGF-β1 induces HO-1 and MIF expression in cultured wild-type (WT) and Nrf2 deficient (KO) mouse aortic smooth muscle cells (MASMC). In addition, nuclear translocation of Nrf2 and p53, a transcription factor which mediates apoptosis, were investigated in human aortic smooth muscle cells (HASMC) treated with TGF-β1. Western blot analyses revealed that HO-1 and MIF expression were significantly enhanced by TGF-β1 (0-10ng/ml, 0-12 h, p<0.01, n=5) in WT but not Nrf2 KO MASMC. Induction of HO-1 in HASMC by TGF-β1 (5 ng/ml, 12 h) was significantly (p<0.05, n=3) attenuated by scavenging of superoxide by superdoxide dismutase (200 U/ml) or following inhibition of NADPH oxidase by diphenylionium (2 μM). TGF-β1 (0-10 ng/ml, 2h) elicited significant (p<0.05, n-3) nuclear translocation of Nrf2 and attenuated nuclear accumulation of p53 in response to hydrogen peroxide generated by glucose oxidase (10 mU/ml, 2h) in HASMC. Our novel findings suggest that TGF-β1 may afford protection in aortic SMC by enhancing Nrf2 mediated induction of cytoprotective antioxidant genes such as HO-1 and MIF and attenuating p53 activation in response to oxidative stress. Therapeutic strategies to modulate TGF-β1 in the vessel wall may be of benefit in atherogenesis and restenosis.