Plasminogen activator inhibitor type 1 (PAI-1), produced partly from liver is a risk factor for macrovascular and microvascular complications of diabetes. Ghrelin, a recently described orexigenic peptide hormone, attenuates PAI-1 induced by TNF-α in the human hepatoma cell line (HepG2). Exposure to TNF-α (1 ng/ml) for 24 h caused a significant increase in PAI-1 mRNA expression and protein secretion, as evaluated by RT-PCR and ELISA, but pretreatment with ghrelin (1–100 ng/ml) inhibited both basal and TNF-α-induced PAI-1 release in a dose and time-dependent manner in HepG2. PDTC, selective NF-κB inhibitor, had no additive inhibitory effects with ghrelin. The results indicate that ghrelin inhibits both basal and TNF-α-induced PAI-1 production via NF-κB pathway in HepG2 cells, and suggest that the peptide plays a therapeutic role in atherosclerosis, especially in obese patients with insulin resistance, in whom ghrelin levels were reduced.