Fructose has been considered as an alternative sweetener to sucrose because it results in less glycemia when given to normal subjects or to those with mild noninsulin-dependent diabetes mellitus. Oral fructose also results in efficient glycogen synthesis. However, multiple hepatotoxic effects have been reported following parenteral fructose administration. We have examined the effects of large oral fructose and glucose loads (4 g/kg) and of graded intravenous fructose doses (50-500 mg/kg) on hepatic metabolism and glycogen synthesis in normal, fasted rats. Fructose was absorbed more slowly than glucose when given by gavage (59% vs 91% absorbed in 120 min). Oral fructose administration resulted in greater liver and muscle glycogen synthesis, despite smaller increases in plasma glucose and insulin concentrations, than was found after oral glucose administration. Increases in percent glycogen synthase I (active form) occurred after both oral fructose and glucose loads (67% vs 115% increase). There was no evidence of hepatotoxicity even after a very large oral fructose load. When small (less than or equal to 125 mg/kg) iv doses of fructose were given, the portal vein fructose concentration remained less than or equal to that found after oral fructose administration (1.1 mM). The percent synthase I increased up to threefold, and there was no evidence of hepatotoxicity. Larger iv doses resulted in a fall in percent synthase I, an increase in percent phosphorylase a, and inorganic phosphate and nucleotide depletion. We conclude that the slow absorption of an oral fructose load prevents hepatotoxic effects and permits efficient glycogen synthesis.