Intake of fructose-containing sugars is strongly associated with metabolic syndrome. Compared with other sugars, dietary fructose is uniquely metabolized by fructokinase. However, the tissue-specific role of fructokinase in sugar-induced metabolic syndrome, and the specific roles of glucose and fructose in driving it, is not fully understood. Here, we show that in mice receiving excess fructose-glucose solutions, whole-body deletion of fructokinase, and thus full blockade of fructose metabolism, is sufficient to prevent metabolic syndrome. This protection is not only due to reduced fructose metabolism, but also due to decreased sugar intake. Furthermore, by using tissue-specific fructokinase-deficient mice, we determined that while sugar intake is controlled by intestinal fructokinase activity, metabolic syndrome is driven by fructose metabolism in the liver. Our findings show a two-pronged role for fructose metabolism in sugar-induced metabolic syndrome, one arm via the intestine that mediates sugar intake and a second arm in the liver that drives metabolic dysfunction.