Objective: Orexins (hypocretins) are neuropeptides expressed in hypothalamic neurons and have regulatory roles in feeding/drinking behaviours, endocrine functions and sleep/wakefulness state. Major depressive disorder (MDD) is a major mood disorder and neurotransmitter dysfunction in hypothalamic neurons may have roles in its formation. Hence, we conducted experiments to determine whether orexin receptor 1 and 2 (Orx(1), Orx(2)) genes were associated with MDD development. Methods: Seventy-five MDD patients and 87 healthy controls were enrolled for the study. Genotyping was carried out with real-time polymerase chain reaction (RT-PCR). Hamilton Rating-Scale for Depression (HRSD) and Beck Depression Inventory (BDI) were utilized to evaluate depressive symptom severity. Results: A significant relation was found in genotype frequencies of Orx(1) rs10914456 and rs2271933 variants between MDD patients and controls (p = .009, p = .006). Rs10914456 CC genotype increased MDD risk 3.57 times more than carrying other genotypes (p = .008, OR =3.57;95% CI: 1.39-9.14). However, no association was observed in Orx(2) rs2653349 genotypes for MDD development (p > .05). Although statistically not significant, HRSD scores were diminished in MDD subjects carrying rs10914456 CC variants when compared with CT and TT variants (p = .069). Conclusion. This study suggests that, Orx(1) rs10914456 and rs2271933 can be associated with MDD development. Hence, Orx(1) rs10914456 variants may affect depressive symptom severity.