To investigate the pathologic change of gallbladder mucosa related to gallstone formation, 52 mice were fed a lithogenic diet containing 1% cholesterol and 0.5% cholic acid and we evaluated the sequential morphologic changes in the gallbladder from two days to 40 weeks. Cholesterol gallstones began to appear after two weeks and all the mice had gallstones after eight weeks. At two days, the mitotic index was at its highest. The gallbladder mucosa showed progressive hyperplastic change with earlier papillary projection of the folds and later inward proliferation. At the same time of stone formation, mucous cells forming glands appeared. Their histochemical profile of mucin was different from that of normal epithelium. Numbers of mucous cells increased gradually until 24 weeks but slightly decreased afterward. These results suggest hyperplasia and metaplasia are closely related to the gallstone formation. Hyperplasia is probably reactive to irritating effect of lithogenic bile or stone. Metaplasia and cholesterol gallstone may develop simultaneously, and act synergistically.