Background: Job burnout is a stress-related syndrome influenced by both genetic and environmental factors. Poor sleep quality acting as a stressor may lead to job burnout. The oxytocin receptor gene (OXTR) related to stress reactivity may also exert an effect on job burnout. We aimed to explore the effect of sleep quality, a functional OXTR rs2268498 polymorphism, and their interaction on job burnout in the Chinese population, which has not been explored yet. Methods: A preliminary study was performed using a cross-sectional design. The Pittsburgh Sleep Quality Index (PSQI) and the Malash Burnout Inventory (MBI) were measured from 575 healthy subjects. The OXTR rs2468498 polymorphism was genotyped in 376 subjects. Results: There were significant main effects of sleep quality (p<0.05), but not of the OXTR rs2468498 genotype on burnout. Interestingly, the interaction between sleep quality and the rs2468498 genotype was significant (p<0.05). In the poor sleep group, the C allele (C/C and T/C) carriers showed higher Emotional Exhaustion level than T homozygotes, while in the good sleep group, the C allele carrier showed a lower Emotional Exhaustion level. Limitations: This study covered subjects from only one university and the sample size for genotyping was relatively small. As we analyzed only the OXTR rs2268498 polymorphism, this study could not reveal the effects of the cerebrospinal oxytocin concentration and the haplotypes. Conclusions: Our findings suggest that the OXTR polymorphism modulates the influence of subjective sleep quality on burnout. We conclude that the C allele of the OXTR rs2468498 polymorphism plays a susceptible role in job burnout.