Although the hepatomitogenic activity of T3 is well established, the wide range of harmful effects exerted by this hormone precludes its use in regenerative therapy. The aim of this study was to investigate whether an agonist of TRβ, KB2115 (Eprotirome), could exert a mitogenic effect in the liver, without most of the adverse T3/TRα-dependent side effects. F-344 rats treated with KB2115 for 1 week displayed a massive increase in bromodeoxyuridine incorporation (from 20% to 40% vs. 5% of controls), which was associated with increased mitotic activity in the absence of significant signs of liver toxicity. Noteworthy, while cardiac hypertrophy typical of T3 was not observed, beneficial effects, such as lowering blood cholesterol levels, were associated to KB2115 administration. Following a single dose of KB2115, hepatocyte proliferation was evident as early as 18 h, demonstrating its direct mitogenic effect. No increase in serum transaminase levels or apoptosis was observed prior to or concomitantly with the S phase. While KB2115-induced mitogenesis was not associated to enhance expression of c-fos, c-jun, and c-myc, cyclin D1 levels rapidly increased. In conclusion, KB2115 induces hepatocyte proliferation without overt toxicity. Hence, this agent may be useful for regenerative therapies in liver transplantation or other surgical settings.