Traditionally, serotonin (5-HT) has been most commonly linked with carbohydrate (CHO) intake. However, in recent years it has been demonstrated that serotoninergic drugs such as dexfenfluramine also reduce energy intake and reverse body weight gain in rats exposed to weight-increasing high-fat diets. Dexfenfluramine is also effective in decreasing food intake and body weight gain of rats that gain weight on a high-fat cafeteria diet. The basic science studies indicate that serotoninergic activity--induced by dexfenfluramine--can act as a sufficient stimulus for the reduction of fat consumption. High-fat diets do not appear to impede the suppressive effect of dexfenfluramine on food intake. In human studies with dexfenfluramine, it has often been the case that the fat content of test foods has been held constant--with only protein and CHO allowed to vary. These studies therefore cannot display any direct effect on fat. However, when food choice is not limited by experimental constraints, a significant reduction of fat intake by dexfenfluramine has been demonstrated in obese patients. In other experimental studies, dexfenfluramine has suppressed fat intake to a greater extent than other macronutrients when free selection of foods has been permitted. Taken together, these studies demonstrate that dexfenfluramine is effective at reducing energy intake with a diet high in fat and may under certain conditions cause a selective avoidance of high-fat foods.