Objectives: This study aimed to clarify the association between circulating pregnancy-associated, placenta-specific microRNAs in the maternal plasma of women with fetal trisomy 18 pregnancies. Materials and Methods: All samples were obtained after receiving written informed consent and the study protocol was approved by the Institutional Review Board. Maternal blood samples (7 ml) were obtained at 16–19 weeks of gestation from 13 pregnant women carrying fetuses with trisomy 18 (trisomy 18 pregnancy group) and from 24 pregnant women carrying fetuses with normal karyotypes (normal karyotype pregnancy group). The plasma concentrations of pregnancy- associated, placenta-specific microRNAs (miR-515-3p, -517a, -517c, and -518b) were measured by quantitative RT-PCR. Results: No significant differences in clinical characteristics were observed between the two groups. miR-515-3p, miR-517a, miR-517c, and miR- 518b were shown to be present in significantly lower plasma concentrations in the trisomy 18 pregnancy group than in the normal karyotype pregnancy group. Plasma concentrations of cell-free miR-517c could distinguish pregnancies with fetal trisomy 18 from those with normal fetal karyotypes, yielding an area under the curve of 0.733 (95% confidence interval: 0.559–0.881). Conclusion: Cell-free pregnancy- associated, placenta-specific microRNAs may therefore be potential molecular markers to estimate the risk of pregnancies with fetal trisomy 18.