To determine whether the administration of small amounts of glucose through an oral spray device (GSD) facilitates weight loss in overweight/obese subjects involved in a lifestyle modification programme. We randomly assigned 56 overweight/obese subjects to either the treatment group (n = 32) or the control group (n = 24). All subjects in both groups followed a structured dietary programme of 6,280.2 kJ (1,500 kcal)/day and exercised minimum 150 min a week and were followed-up for a period of 60 days. Subjects assigned to the treatment group were asked to spray, during early symptoms of neuroglycopenia, 10 puffs by GSD. GSD is a device that delivers to the buccal mucosa 50 mg of glucose per puff. A mean weight loss of 3.5 ± 3.0 kg in GSD-treated group compared to 1.7 ± 2.1 kg in control group (p = 0.01) was observed. Significant differences regarding reduction of BMI (-1.3 ± 1.0 vs. -0.7 ± 0.8 kg/m2; p = 0.01) and waist circumference (-3.5 ± 3.2 vs. -0.9 ± 3.5 cm; p = 0.02) were also detected. A short-term use of GSD, in association with dietary restriction and exercise, is helpful in improving weight loss and in reducing waist circumference in overweight/obese subjects.