Receptors for antipsychotics in the hypothalamus contribute to antipsychotics-induced weight gain; however, many of these receptors are also expressed in the intestine. The role of these intestinally-expressed receptors, and their potential modulation of nutrient absorption, have not been investigated in the context of antipsychotics-induced weight gain. Here we tested the effect of dietary fructose and intestinal fructose uptake on clozapine-induced weight gain in mice. Weight gain was determined in wild type mice and mice lacking the GLUT5 fructose transporter that were “orally-administered” 20mg/kg clozapine for 28 days. To assess the role of dietary fructose, clozapine-treated mice were fed controlled diets with different levels of fructose. Effect of clozapine treatment on intestinal fructose transport activity and expression levels of various receptors that bind clozapine, as well as several genes involved in gluconeogenesis and lipogenesis were measured using real-time RT-PCR and western blotting. Oral administration of clozapine significantly increased body weight in wild type C57BL/6 mice but not in GLUT5 null mice. The clozapine-induced weight gain was proportional to the percentage of fructose in the diet. Clozapine-treated mice increased intestinal fructose uptake without changing the intestinal expression level of GLUT5. Clozapine-treated mice expressed significantly higher levels of intestinal H1 histamine receptor in the wild type but not GLUT5 null mice. Clozapine also increased the intestinal expression of fructokinase and several genes involved in gluconeogenesis and lipogenesis. Our results suggest that increased intestinal absorption and metabolism of fructose contributes to clozapine-induced weight gain. Eliminating dietary fructose might prevent antipsychotics-induced weight gain.