Excess scarring of the conjunctiva after glaucoma filtration surgery is a major cause of failure. Transforming growth factor (TGF)-beta is critically involved in post-operative scarring. Lithium inhibits TGF-beta-induced gene protein expression in corneal fibroblasts and inhibits TGF-beta-induced epithelial mesenchymal transition. Here, we investigated the effects of LiCl on TGF-beta 1-mediated signaling pathways and on myofibroblast transdifferentiation of human Tenon's capsule fibroblasts (HTFs). LiCl treatment reduced expression of TGF-beta 1-induced alpha-SMA expression in HTFs. LiCl also decreased Akt phosphorylation induced by TGF-beta 1. TGF-beta 1-induced alpha-SMA expression was significantly decreased by LY294002 and Akt siRNA indicating that these changes are mediated by the PI3K/Akt pathway. Thus, LiCl induces the suppression of transdifferentiation stimulated by TGF-beta 1 by the regulation of PI3K/Akt signaling in HTFs.