OBJECTIVE Previous animal studies have shown that the oxytocin system might affect glucose homeostasis through the hypothalamus-pituitary-adrenal (HPA) axis and peripheral organs. Moreover, whether the effect is stratified by the polymorphism of oxytocin receptor gene (OXTR) remains unclear. METHODS In this study, we recruited 89 non-diabetic participants. Their plasma oxytocin and serum insulin profiles were obtained, and the polymorphism of OXTR rs53576 was genotyped. RESULTS There were significant correlations between the oxytocin level and fasting glucose level (r = -0.29, P <0.01), insulin level (r = -0.26, P = 0.01), and homeostasis model assessment-estimated insulin resistance (HOMA-IR) (r = -0.25, P = 0.01), when adjusted for age, gender, and body mass index (BMI). When further considering the stratification effects of OXTR variation, we found that the oxytocin level was significantly correlated with the fasting glucose level (r = -0.25, P = 0.04), insulin level (r = -0.35, P = 0.03), and HOMA-IR (r = -0.35, P < 0.01) in subjects with the OXTR A allele (n = 75) after adjustment for age, gender, and BMI. In addition, the oxytocin level in those with the GG genotype of OXTR was significantly negatively correlated with the leptin level (n = 14, r = -0.66, P = 0.02). CONCLUSIONS The results demonstrated that the polymorphism of OXTR plays an important role in individual differences in the correlation of oxytocin and glucose homeostasis in non-diabetic subjects.