Weight loss in obese subjects ingesting very-low-energy (VLE; < 2510 kJ/d), low-fat (< or = 1 g/d) formula diets is associated with liver-function-test abnormalities and gallstone formation. It is unknown whether these abnormalities develop during treatment with diets higher in energy and fat. We prospectively studied liver-function tests and gallstone formation in 73 obese patients ingesting approximately 3500 kJ and 15-25 g fat daily for 10 wk. Two of 53 patients completing the protocol developed ultrasonographic gallstones during weight loss, a rate substantially lower than that observed with VLE diets. Trend analysis demonstrated significant increases in AST and ALT activities, but changes were less than those observed with VLE diets. Patients who developed gallstones had a significantly greater weight loss rate and larger increases in AST and ALT than did nonstone-forming patients. These results suggest that the risk of developing hepatobiliary abnormalities with dieting is lowered when subjects ingest greater amounts of energy and fat than that administered in earlier VLE-diet studies. Our results also highlight potential risk factors and markers of new gallstone formation.