Purpose: Obstructive sleep apnea (OSA) is a common sleep disorder that is influenced by various environmental and genetic factors. The potential associations of leptin and leptin receptor (LEPR) polymorphisms with OSA have been studied in different populations; however, the results remain inconclusive. The aim of this study was to examine the association between LEPR gene polymorphisms and OSA risk. Methods: A total of 322 samples were used, including 226 OSA subjects and 96 controls. Targeted sequencing of the entire LEPR gene was performed in all subjects. Polysomnography was used to diagnose obstructive sleep apnea. The associations between variants and OSA were determined by multivariate regression analyses. Results: Four single-nucleotide polymorphisms of LEPR were identified in all subjects. The genotype frequency of locus rs3790435 was significantly different between the OSA and control groups. Specifically, the variant genotype rs3790435 CC in LEPR was associated with a lower risk of OSA (OR 0.462, 95% CI 0.250–0.854, p = 0.014) in a recessive model after controlling for potential confounders. After BMI stratification, obese patients with this variant genotype were found to have a lower risk of developing OSA. Moreover, subjects with the rs3790435 CC genotype were found to have a statistically lower apnea–hypopnea index (AHI) and higher nadir oxygen saturation than the TT/CC genotypes without differences in plasma leptin levels. Conclusions: Our study identified a novel variant of LEPR in patients with OSA, and specifically found an association between rs3790435 polymorphisms and OSA risk in Chinese Han subjects. © 2019, The Author(s).