Preterm birth (PTB) is a predominant contributor to neonatal mortality and morbidity worldwide. However, the pathophysiology of PTB is not well-understood. We tested the hypothesis that single-nucleotide polymorphisms (SNPs) in the placenta-derived MHC class I chain-related gene A (MICA) could disrupt placental development and hence result in PTB. Nineteen selected SNPs in MICA were genotyped in a case-control study of 127 premature infants and 634 term controls in a Chinese Han population. We found that significantly increased PTB risk was associated with homozygosity for the A variant of rs2256318 (adjusted odds ratio = 6.97 and 95% confidence interval = 2.34-20.74 for A/A, compared with G/G genotype, P = 0.001). In addition, the A/A genotype of rs2256318 was associated with decreased placental weight of neonates (β = -25.331; P = 0.033). Furthermore, stratified analysis demonstrated that the A/A genotype of rs2256318 was associated with increased PTB risk in female group. In addition, we observed statistical interaction between the polymorphism rs2516448 and sex (P = 0.04). No significant differences in the distribution of haplotypes between cases and controls were detected. Our results indicate that the polymorphism of rs2256318 in MICA may contribute to the etiology of PTB through interfering with placental development. These findings need to be further validated in larger and multi-ethnic populations.