Objective: This study aims to evaluate the plasma levels of neuropeptide-Y (NPY), leptin and ghrelin and in children with attention deficit hyperactivity disorder (ADHD) and investigate the neurobiological mechanisms beneath side effects of methylphenidate such as lack of appetite, weight loss and/or decrease in weight gain. Methods: Thirty children diagnosed as ADHD with DSM-5 and 21 healthy children similar to study group with age and gender were included in the study. All subjects are evaluated with Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version (K-SADS-PL). All parents filled sociodemographic data form, also parents of the chil-dren with ADHD filled Conners Parent Rating Scale (CPRS). ADHD group evaluated with Barkley Stimulant Side Effect Evaluation Form after two months of extended release methylphenidate (OROS-MPH) therapy. Plasma NPY, leptin and ghrelin levels were evaluated in control group for once and in ADHD group for twice, before and 2 months after treatment with enzyme-like immune-sorbent assay (ELISA) kits. Results: In our study, when plasma leptin, ghrelin and NPY levels of healthy controls and ADHD group were compared; NPY level was lower in the ADHD group. Compared with healthy controls, post-treatment ADHD group leptin level was observed to be lower. In the ADHD group, only NPY level was found to be higher after treatment than before treatment. Conclusion: It was observed that NPY levels were found to be lower in the ADHD group than in the healthy group, and plasma levels increased after treatment. In addition, leptin and ghrelin levels not changed after treatment. Thus, further studies with larger study groups are needed whether these changes will be more meaningful when the treatment duration is prolonged. New studies may reveal neurobiological mechanisms beneath loss of appetite and/or weight loss associated with methylphenidate treatment. [Anadolu Psikiyatri Derg 2018; 19(5.000): 485-492]