Transforming growth factor betas (TGF-betas) are multifunctional polypeptides that either inhibit or stimulate cell proliferation. They mediate their functions through their signaling receptors. Clinically, hepatolithiasis has been regarded as a risk factor for cholangiocarcinoma. The aim of this study was to examine the expression of TGF-betas and their receptors in stone-containing intrahepatic bile ducts (IHD) and cholangiocarcinoma and try to predict whether hepatolithiasis has a predisposition to development of cholangiocarcinoma. Twenty-eight surgically resected specimens of stone-containing IHD and 15 specimens of cholangiocarcinoma were subjects for this study. Immunohistochemical analysis was done on three TGF-betas and their signaling receptors to check their expression in non-neoplastic and neoplastic bile ducts. No immunoreactivity of TGF-beta(1) was found in any specimens. The overexpression of TGF-beta(2) and TGF-beta(3) was found in both hepatolithiasis (93%-100%) and cholangiocarcinoma (80%) at levels significantly higher than those of normal controls (10%-20%) ( p< 0.001). The immunoreactivity of type I receptor (T beta RI) and type II receptor (T beta RII) also showed increased expression in stone-containing IHD, whereas T beta RII was absent in cholangiocarcinoma. We conclude that the overexpression of TGF-beta(2) and TGF-beta(3) and the absence of T beta RII in cholangiocarcinoma could lead to enhanced tumor cell proliferation. At the same time, the overexpression of TGF-betas and their receptors in stone-containing IHD could suggest a close relationship between hepatolithiasis and cholangiocarcinoma.