Large interindividual variation is characteristic of the cephalic-phase insulin response (CPIR). Our aim was to examine the largely unknown determinants of CPIR in obese nondiabetic subjects before and after weight reduction. After a 12-hour overnight fast, 20 healthy, obese (body mass index, 31.1 to 41.4 kg/m2) subjects were individually exposed to food without being allowed to eat it. Levels of insulin, glucose, C-peptide, free fatty acids, and salivation, together with assessments of feeling of hunger and desire to eat, were measured during the experiment. Subjects were divided into three groups according to CPIR before the weight reduction: positive (PR), intermediate (IR), and negative (NR) responders. CPIR measurements before and after weight reduction correlated significantly with each other (r = .61, P < . 01,n=18). At the beginning of the study, NR had higher fasting plasma glucose and insulin values, as well as higher postload plasma glucose values, as compared with PR and IR. These differences disappeared after weight reduction. In an intravenous glucose tolerance test (IVGTT) performed 9 to 12 months afterward, first-phase insulin secretion was significantly lower in NR. Thus, the negative CPIR during visual and olfactory exposure to food-related stimuli may be related to the attenuated first-phase insulin secretion and mildly impaired glucose metabolism, possibly related to insulin resistance.