Objective To explore the relationship between the SP-B exon 4 (T131I) and susceptibility of neonatal respiratory distress syndrome (NRDS) in Western Inner Mongolia. Methods A case control study from September 2009 to February 2016 in the Affiliated Hospital of Inner Mongolia Medical University neonatal ward was performed. Eighty-six preterm infants of Mongol nationality suffered from NRDS were selected as the case group, while eighty-six preterms in the same period without NRDS were selected as the control group. Polymerase chain reaction were used to detect mutations in exon 4 of SP-B, genotype, and allelic distribution of T131I of exon 4, as well. Results  Newborns in western Inner Mongolia: ①No mutation was found in SP-B exon 4. ②The frequencies of genotype CC, CT and TT of T131I in the NRDS group were 58.1%、27.9% and 14.0%, respectively. Frequency of allele C were 80.2%, and frequency of allele T were 19.8%.  In the control group,?the frequencies of genotype CC, CT and TT were 40.7%、43.0% and 16.3%, respectively. Frequency of allele C were 64.0%, and frequency of allele T were 36.0%, there was significant difference in the frequencies of SP-B exon 4 T131I sites between these two groups (P < 0.05). Conclusion There was no mutation found in SP-B exon 4. Exon 4 (T131I) gene polymorphism of SP-B gene may be one of the susceptible locus of Mongolian infants in the western region of Inner Mongolia.