Background: Preterm birth is associated with an increased risk of neonatal complications and death, as well as poor health and disease later in life. Epigenetics could contribute to the mechanism underlying preterm birth. Results: Genome-wide DNA methylation analysis of whole blood cells from ten women was performed using an Illumina In nium HumanMethylation450 BeadChips array. We identi ed 1,581 differentially methylated CpG sites in promotor regions between term and preterm birth. Although the differences were not signi cant after correcting for multiple tests, seven CpGs on the genomically imprinted VTRNA2-1 showed the largest differences (range: 26-39%). Pyrosequencing veri cation was performed with blood samples from pregnant women recruited additionally (n = 82). In total, 28 (34.1%) cases showed hypomethylation of the VTRNA2-1 promoter (< 13% methylation), while 54 cases (65.9%) showed a methylation level of 30-60%. Hypermethylation of VTRNA2-1 was associated with an increased risk of preterm birth after adjusting for maternal age, season of delivery, parity and white blood cell count. The mRNA expression of VTRNA2-1 was 0.51-fold lower in women with preterm deliveries (n = 20) compared with women with term deliveries (n = 20). Conclusions: Our results suggest that changes in VTRNA2-1 methylation in maternal blood are related to preterm birth. Further studies are needed to con rm the association of VTRNA2-1 methylation with preterm birth in a large population, and to elucidate the underlying mechanism.