Background: Ghrelin and leptin recently emerged as the most influential neuroendocrine factors in the pathophysiology of obesity. The said peptides act in reciprocity and are responsible for regulation of appetite and energy metabolism. Intragastric balloons acquired worldwide popularity for obesity treatment. However, the roles of ghrelin and leptin in intragastric balloon treatment were still not systematically studied. Methods: A prospective single-center study included 43 Caucasians treated with BioEnterics intragastric balloon, with age range of 18–60, and divided to non-morbid (body mass index cutoff 40 kg/m2) or morbid type of obesity, with 12 months follow-up. Serum hormonal samples were taken from fasting patients and kept frozen until analyses. Results: Significant differences were observed in anthropometrics and there were no differences between genders or comorbidities. The baseline weight for non-morbid vs. morbid was 104 kg (90–135) vs. 128.5 kg (104–197). Weight loss was statistically different between the studied groups during the study course with a median control weight at 6 months of 92 kg (72–121) vs. 107 kg (84–163), p<0.001. Treatment was successful for 18 (94.7%) vs. 16 (66.7%) patients, p= 0.026. Ghrelin varied from 333.3 to 3,416.8 pg/ml and leptin from 1.7 to 61.2 ng/ml, with a statistically significant time dependent relationship. A significant difference (p=0.04) with emphasized ghrelin peak was found in the 3rd month of treatment for non-morbidly obese subjects. Conclusions: The importance of ghrelin and leptin in treatment-induced changes was reaffirmed. Ghrelin hyperresponse in non-morbidly obese subjects characterized greater short-term treatment efficiency and landmarked an inclination to weight regain. The results suggest a potential pattern of individualization between obese patients according to body mass index towards intragastric balloon or bariatric surgery. Further studies are needed in order to get better insights in the pathophysiologic mechanisms of obesity.