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Problem: Immune and inflammatory responses are known to be major causes of preterm birth (PTB). The maternal genetic background plays an important role in the development of PTB. Interferon‐stimulated gene 15 (ISG15) is an interferon‐induced protein which can modulate immune cell activation and function. We aim to study if polymorphisms in the ISG15 gene are associated with spontaneous PTB (sPTB) risk in Taiwanese women. Method of study: ISG15 rs4615788 C/G, rs1921 G/A, and rs8997 A/G polymorphisms were genotyped in a hospital‐based study of 112 women with sPTB and 1120 term controls. The plasma concentrations of ISG15 were determined by enzyme‐linked immunosorbent assay. Results: We found the ISG15 rs1921 G‐rs8997 A haplotype was associated with decreased risk for PTB (χ2 = 6.26, p =.01, pc =.04). The A/G genotype of ISG15 rs8997 polymorphism might have the potential to confer reduced risk of PTB women (χ2 = 4.09, p =.04, pc =.08). Spontaneous PTB women displayed higher plasma ISG15 levels compared to term controls (p <.001). The plasma ISG15 levels among pregnant women with rs8997 A/G genotype were found significantly lower compared to G/G genotype (p =.03). Conclusions: Women with the ISG15 rs1921 G‐rs8997 A haplotype may associate with spontaneous PTB. These findings provide new insights into the etiology of preterm birth. [ABSTRACT FROM AUTHOR]