The beneficial effects of simvastatin on fibrosis in various organs have been reported. In addition, bone marrow (BM)-derived mesenchymal stem cells (MSCs) have been suggested as an effective therapy for hepatic fibrosis and cirrhosis. Recent evidence suggests that pharmacological treatment devoted to regulating stem cell function is a potential new therapeutic strategy that is drawing nearer to clinical practice. The aim of this study was to determine whether the combination treatment of simvastatin plus MSCs (Sim-MSCs) could have a synergistic effect on hepatic fibrosis in a thioacetamide (TAA)-induced cirrhotic rat model and hepatic stellate cells (HSCs). Cirrhotic livers from rats treated with Sim-MSCs exhibited histological improvement compared to those treated with simvastatin alone. Sim-MSCs combination treatment decreased hepatic collagen distribution, lowered the hydroxyproline content, and rescued liver function impairment in rats with TAA-induced cirrhosis. These protective effects were more potent with Sim-MSCs than with simvastatin alone. The upregulation of collagen-1, alpha-smooth muscle actin (alpha-SMA), transforming growth factor (TGF)-beta 1, and phospho-Smad3 in cirrhotic livers was prevented by the administration of Sim-MSCs. Intriguingly, Sim-MSCs inhibited both TGF-beta/Smad3 signaling and alpha-SMA in HSCs. The Sim-MSCs combination treatment exerted strong protective effects against hepatic fibrosis by suppressing TGF-beta/Smad signaling. Simvastatin could act synergistically with MSCs as an efficient therapeutic approach for intractable cirrhosis. (C) 2018 Elsevier Inc. All rights reserved.