Unlike dietary-induced cholesterol gallstones, which may disappear spontaneously when the lithogenic diet is withdrawn, little is known about the natural history of pigment gallstones. We examined whether pigment gallstone disease, which can be uniformly induced in the dog by six weeks of a methionine-deficient diet, can be reversed by return to normal diet. As previously reported, all dogs develop pigment gallstones as well as significant increases in biliary total calcium, free ionized calcium, and cholesterol concentrations after six weeks of a lithogenic diet. These changes are accompanied by a significant increase in the concentration of unconjugated bile salts in bile. In addition, histologic changes in the gallbladder wall occur that are consistent with a moderate degree of chronic cholecystitis. This study clearly demonstrates that return to a normal diet for six weeks allows bile composition to normalize, gallstones to disappear in 50% of dogs, and gallbladder histologic changes to return toward normal. Thus, it would appear that pigment gallstone disease in this model may be reversible, at least early during its course. Although the relevance of these findings to pigment gallstones in humans must be established, the potential for nonoperative treatment of pigment gallstones should not be discounted.